Compounds for the treatment of inflammatory diseases

ABSTRACT

Dihydrothienopyrimidines of formula 1  
                 
and the pharmacologically acceptable salts, enantiomers, racemates, hydrates, or solvates thereof, which are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin, or eyes, diseases of the peripheral or central nervous system or cancers, as well as pharmaceutical compositions which contain these compounds.

RELATED APPLICATIONS

This application claims priority to German Application No. DE 10 2005019 201.7, filed Apr. 21, 2005, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The invention relates to new dihydrothienopyrimidines of formula 1, andthe pharmacologically acceptable salts, pharmacologically acceptablesalts, diastereomers, enantiomers, racemates, hydrates, or solvatesthereof,

which are suitable for the treatment of respiratory or gastrointestinalcomplaints or diseases, inflammatory diseases of the joints, skin, oreyes, diseases of the peripheral or central nervous system or cancers,as well as pharmaceutical compositions which contain these compounds.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 3,318,881 and BE 663693 disclose the preparation ofdihydrothieno[3,2-d]pyrimidines which have cardiovascular and sedativeproperties.

SUMMARY OF THE INVENTION

Surprisingly it has now been found that dihydrothienopyrimidines offormula 1 are suitable for the treatment of inflammatory diseases. Thepresent invention therefore relates to compounds of formula 1

-   -   wherein:    -   X denotes O, S, SO, or SO₂;    -   R¹ denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene, or        C₅₋₁₀-heteroaryl-C₁₋₆-alkylene;    -   R² denotes H or an optionally mono- or polysubstituted group        selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, an        optionally mono- or poly-bridged mono- or bicyclic        C₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, an aromatic or non-aromatic,        heterocyclic C₃₋₁₀ ring, a bicyclic ring, and a C₆₋₁₀-aryl fused        to a C₃₋₁₀ heterocycle; or    -   NR¹R² together denote a heterocyclic ring which is optionally        substituted by one or more groups selected from C₁₋₄-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, straight-chain or branched        C₁₋₆-alkanol, and oxo;    -   R³ denotes a mono- or polysubstituted group selected from among        a heterocyclic C₆₋₁₀ ring, C₃₋₇-cycloalkyl,        C₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, a        fused, bicyclic ring which may optionally contain 1-4        heteroatoms selected independently of one another from N, O, or        S, or    -   R³ denotes optionally substituted phenyl, or    -   R³ denotes a group COR^(3.7), COCH₂R^(3.8), CONHR^(3.8), or        SO₂R^(3.8), wherein:        -   R^(3.7) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            or C₆₋₁₀-aryl;        -   R^(3.8) denotes C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            C₃₋₇-cycloalkyl, or a group selected from among C₆₋₁₀-aryl,            a heterocyclic C₃₋₁₀ ring, and a bicyclic ring, which is            optionally substituted by one or more groups selected from            among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, halogen,            NR^(3.8.1)R^(3.8.2), C₆₋₁₀-aryl, and a heterocyclic C₃₋₁₀            ring, wherein:            -   R^(3.8.1) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or                C₂₋₆-alkynyl, and            -   R^(3.8.2) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or                C₂₋₆-alkynyl;    -   R⁴ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, or oxo;    -   R⁵ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, or C₂₋₄-alkynyl;    -   R⁶ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, or C₂₋₄-alkynyl;    -   R⁷ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,        C₆₋₁₀-aryl, or OH;    -   R⁸ denotes H, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl,        C₆₋₁₀-aryl, or OH; or    -   R⁷ and R⁸ together form oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Preferred compounds of formula 1 above are those wherein:

-   -   X denotes O, S, SO, or SO₂;    -   R¹ denotes H, C₁₋₆-alkyl, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene,        or C₅₋₁₀-heteroaryl-C₁₋₆-alkylene,    -   R² denotes H or C₁₋₆-alkyl, which may optionally be substituted        by one or more groups selected from among C₁₋₆-haloalkyl, CN,        OR^(2.1), NR^(2.1)R^(2.2), COOR^(2.1), CONR^(2.1)R^(2.2),        C₃₋₇-cycloalkyl optionally substituted by C₁₋₄-alkyl or oxo, an        aromatic or non-aromatic heterocycle optionally substituted by        C₁₋₄-alkyl, oxo, OH, or halogen, C₆₋₁₀-aryl optionally        substituted by C₁₋₄-alkyl or oxo and C₆₋₁₀-aryl fused to a C₅₋₆        heterocycle, while this fused ring system may optionally be        substituted by C₁₋₄-alkyl or oxo, wherein:        -   R^(2.1) denotes H or C₁₋₆-alkyl which is optionally            substituted by a C₃₋₇-cycloalkyl, C₃₋₁₀ heterocycle, or            C₆₋₁₀-aryl, each of which is optionally substituted, and        -   R^(2.2) denotes H or C₁₋₆-alkyl; or    -   R² denotes a group selected from optionally mono- or        poly-bridged C₃₋₁₀-cycloalkyl or a C₃₋₁₀-cycloalkyl, which may        optionally be fused to a C₆₋₁₀-aryl ring which is optionally        substituted by one or more groups selected from among        C₁₋₆-alkyl, OH, CH₂OR^(2.3), COOR^(2.3), COR^(2.3),        CONR^(2.3)R²W⁴, O—C₁₋₆-alkyl, O—C₇₋₁₁-aralkyl, NR^(2.3)R^(2.4),        and NHCOR^(2.5), wherein:        -   R^(2.3) is H or a heterocycle or a C_(1.6)-alkyl, which may            optionally be substituted by a group selected from            C₃₋₇-cycloalkyl, C₃₋₁₀ heterocycle, and C₆₋₁₀-aryl, while            this group may optionally be substituted in each case by one            or more groups selected from among C₁₋₆-alkyl, halogen, OH,            and O—C₁₋₆-alkyl, wherein        -   R^(2.4) denotes H or C₁₋₆-alkyl, and        -   R^(2.5) denotes a group selected from among C₃₋₇-cycloalkyl,            a heterocyclic C₃₋₁₀ ring, and C₁₋₆-alkyl, which may            optionally be substituted by OH; or    -   R² denotes a group of formula 1a    -    Y denotes C₁₋₆-alkylene, optionally substituted by one or two        R^(2.7), wherein R^(2.7) are in each case selected independently        of one another from C₁₋₆-alkyl, COOH, CONH₂, OR^(2.1), and        COOR^(2.1); or R^(2.7) together with one or two carbon atoms of        Y forms a carbocyclic ring with 3 carbon atoms, or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by        one or more groups selected independently of one another from        among C_(1.6)-alkyl, C_(1.6)-haloalkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, CN, halogen, OR²F⁸, COOR^(2.8), COR^(2.10),        NHCOMe, CONR^(2.3)R^(2.4), a C₁₋₄ alkylene group substituted by        NR²F R^(2.2), or NR^(2.1)R^(2.2), or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by        one or more groups selected independently of one another from        among C₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene,        C₃₋₇-cycloalkyl, a C₃₋₇-cycloalkyl-C₁₋₄-alkylene, C₆₋₁₀-aryl,        and a heterocyclic C₃₋₁₀ ring, while these groups may each        optionally be substituted by one or more groups selected from        C₁₋₆-alkyl, C₁₋₆-haloalkyl, COOR^(2.8), CN, halogen, OR^(2.8),        NHCOR^(2.8), oxo, a C₃₋₁₀ heterocycle, a C₃₋₇-cycloalkyl-C₁₋₄        alkylene, a C₅₋₁₀ heterocycle-C₁₋₄-alkylene, and a        NR^(2.1)R^(2.2)—C₁₋₄ alkylene, wherein:        -   R^(2.8) denotes H, C₁₋₆-alkyl, C₆₋₁₀-aryl, a            NR^(2.1)R^(2.2)—C₁₋₄ alkylene group, and        -   R^(2.10) denotes NHR^(2.10.1) or a heterocyclic C₃₋₁₀ ring            which may optionally be substituted by C₁₋₄-alkyl, and        -   R^(2.10.1) denotes H, C₃₋₇-cycloalkyl, C₂₋₆-alkenyl,            C₂₋₆-alkynyl, C₁₋₆-alkyl, or C₁₋₆-alkyl-O—C₁₋₄-alkyl, or    -   R² denotes C₆₋₁₀-aryl, to which an aromatic or non-aromatic        C₃₋₁₀ heterocycle is fused; or R² denotes an aromatic or        non-aromatic heterocyclic C₃₋₁₀ ring which may optionally be        substituted by one or more groups selected from among halogen,        OH, oxo, CN, C₁₋₆-alkyl, C₁₋₆-alkanol, C₆₋₁₀-aryl-C₁₋₆-alkylene,        C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, COR^(2.11),        C₃₋₇-cycloalkyl-C₁₋₄-alkylene, and C₃₋₁₀        heterocycle-C₁₋₄-alkylene, wherein:        -   R^(2.11) denotes a group selected from among C₃₋₁₀            heterocycle-C₁₋₄-alkylene, C₃₋₇-cycloalkyl, and a            heterocyclic aromatic or non-aromatic C₃₋₁₀ ring, which may            optionally be substituted by C₁₋₆-alkyl, which may in turn            optionally be substituted by OH, CH₂OH, OMe, NH₂, a C₃₋₁₀            heterocycle, or NHCOO-^(t)Bu; or    -   R² denotes a group selected from among C₂₋₆-alkenyl or a        bicyclic ring, which may optionally be substituted by methyl; or    -   NR¹R² denotes a heterocyclic ring which may optionally be        substituted by one or more groups selected from among        C₁₋₄-alkyl, OH, and C₁₋₄-alkanol;    -   R³ denotes a group selected from among a heterocyclic C₃₋₁₀        ring, a C₃₋₇-cycloalkyl, a bicyclic, fused aromatic or        non-aromatic ring system, which optionally contains 1 to 4        heteroatoms selected from S, N, or O, or it denotes        C₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, and        CH₂-benzo[1,3]dioxolyl, which may optionally be substituted by        one or more groups selected from OH, halogen, C₁₋₆-alkyl,        O—C₁₋₆-alkyl, C₁₋₆-haloalkyl, and CO—R^(3.1), or    -   R³ denotes phenyl, which may optionally be substituted by one or        more groups selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, C₁₋₄-haloalkyl, C₁₋₆-alkylene-NR^(3.1)R^(3.2), CN,        COOR^(3.1), CONR^(3.1)R^(3.2), NR^(3.1)R^(3.2). NHCOR^(3.1),        CF₃, OR^(3.1), halogen, NHCOR^(3.1), NO₂, SO₂NR^(3.1)R^(3.2),        and C₁₋₆-alkylene-NHCOR^(3.1), wherein:        -   R^(3.1) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl, optionally bridged, mono- or bicyclic C₃₋₁₀            heterocycle, or C₃₋₁₀ heterocycle-C₁₋₄-alkylene group;        -   R^(3.2) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl; or    -   R³ denotes a group of formula 1b        -   R^(3.3) denotes a group selected from among a heterocyclic            C₃₋₁₀ ring which may optionally be substituted by one or            more groups selected from among C₁₋₆-alkyl, oxo,            COR^(3.3.1), COR^(3.3.2), C₁₋₆-alkylene-R^(3.3.2),            CH₂COpyrrolidine, and a heterocyclic C₃₋₁₀ ring, wherein a            sulfur atom optionally contained in the heterocyclic ring,            may optionally be in the form of the oxide or dioxide,            wherein:            -   R^(3.3.1) denotes C₁₋₆-alkyl;            -   R^(3.3.2) denotes NH₂, NH(C₁₋₆-alkyl), N(C₁₋₆-alkyl)₂;                or        -   R^(3.3) denotes a bicyclic ring or heterocyclic spiro ring;            or    -   R³ denotes a group of formula 1c        -   A may be a bond or C₁₋₆-alkyl, which may optionally be            substituted by oxo or NMe₂;        -   R^(3.4) denotes H or C₁₋₆-alkyl;        -   R^(3.5)denotes a group selected from among            -   C₁₋₆-alkyl, which may optionally be substituted by one                or more groups selected from C₃₋₇-cycloalkyl,                C₆₋₁₀-aryl, and a C₃₋₁₀ heterocycle, while this group                may also optionally be substituted in each case by a                group selected from among OH, oxo, C₁₋₆-alkyl,                O—C₁₋₆-alkyl, and C₁₋₆-haloalkyl, or            -   a group selected from a heterocyclic C₃₋₁₀ ring and a                bicyclic ring, which is optionally substituted by one or                more groups selected independently of one another from                among oxo, C₁₋₆-alkyl, OH, C₆₋₁₀-aryl, a heterocyclic                C₃₋₁₀ ring, C₁₋₆-alkylene-R^(3.5.1),                O—C₁₋₆-alkylene-R^(3.5.1), and                NH—C₁₋₆-alkylene-R^(3.5.1), wherein R^(3.5.1) denotes a                group selected from among C₆₋₁₀-aryl and a heterocyclic                C₃₋₁₀ ring which may optionally be substituted by                C₁₋₆-alkyl; or    -   R³ denotes a group of formula 1d        -   D denotes C₂₋₄-alkynyl; an optionally bridged, bicyclic            C₃₋₁₀-cycloalkyl group, which may optionally be substituted            by one or more groups selected from C₁₋₆-alkyl, halogen, OH,            C₁₋₆-haloalkyl, and O—C₁₋₆-alkyl, and        -   R^(3.6) denotes pyridinyl; or    -   R³ denotes a group selected from among COR^(3.7), COCH₂R^(3.8),        CONHR^(3.8), SO₂R^(3.8), and a heterocyclic group fused to a        C₆₋₁₀-aryl group, which may optionally be substituted by methyl,        or    -   R³ denotes a group of formula 1e        -   R^(3.7) denotes H, C₁₋₆-alkyl, C₆₋₁₀-aryl;        -   R^(3.8) denotes a group selected from among C₁₋₆-alkyl,            C₃₋₇-cycloalkyl, or a group selected from among C₆₋₁₀-aryl,            a heterocyclic C₃₋₁₀ ring, and a bicyclic ring, which may            optionally be substituted by one or more groups selected            from among C₁₋₆-alkyl, halogen, NR^(3.8.1)R^(3.8.2),            C₆₋₁₀-aryl, and a heterocyclic C₃₋₁₀ ring;            -   R^(3.8.1) denotes H or C₁₋₆-alkyl;            -   R^(3.8.2) denotes H or C₁₋₆-alkyl;    -   R⁴ denotes H, C₁₋₄-alkyl, or oxo;    -   R⁵ denotes H or C₁₋₄-alkyl;    -   R⁶ denotes H or C₁₋₄-alkyl;    -   R⁷ denotes H, C₁₋₄-alkyl, C₆₋₁₀-aryl, or OH;    -   R⁸ denotes H, C₁₋₄-alkyl, C₆₋₁₀-aryl, or OH; or    -   R⁷ and R⁸ together form oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Preferred compounds of formula 1 above are those wherein

-   -   X denotes O, S, SO, or SO₂; preferably S, SO, or SO₂;    -   R¹ denotes H, C₁₋₄-alkyl;    -   R² denotes H or C₁₋₆-alkyl, optionally substituted by a group        selected from among C₁₋₄-haloalkyl, CN, OR^(2.1),        NR^(2.1)R^(2.2), COOR^(2.1), and CONR^(2.1)R^(2.2) or optionally        substituted by a group selected from among C₃₋₇-cycloalkyl,        C₆₋₁₀-aryl, and a heterocyclic, aromatic C₅₋₁₀ ring, optionally        substituted by methyl or oxo;        -   R^(2.1) denotes H or C₁₋₄-alkyl;        -   R^(2.2) denotes H or C₁₋₄-alkyl; or    -   R² denotes C₃₋₇-cycloalkyl, optionally substituted by a group        selected from among C₁₋₄-alkyl, CH₂OR^(2.3), COOR^(2.3),        CONR^(2.3)R^(2.4), O-benzyl, NR^(2.3)R^(2.4), or NHCOR^(2.5),        -   R^(2.3) denotes H or C₂₋₄-alkyl,        -   R^(2.4) denotes H or C₁₋₄-alkyl, and        -   R^(2.5) denotes C₃₋₇-cycloalkyl, a heterocyclic, aromatic            C₅₋₁₀ ring, or C₁₋₆-alkyl, optionally substituted by OH; or    -   R² denotes a group of formula 1a        -   Y denotes C₁₋₄-alkylene, optionally substituted by one or            two R^(2.7)        -   m denotes 0, 1, 2;        -   R^(2.7) each independently of one another denote C₁₋₄-alkyl,            COOH, CONH₂; or together with one or two carbon atoms of Y            forms a carbocyclic ring with 3 carbon atoms, or    -   R² denotes C₆₋₁₀-aryl, optionally substituted by one or more        groups selected from among C₁₋₄-alkyl, CN, halogen, OR^(2.8),        COOR^(2.8), COR^(2.10), and NHCOMe,        -   R^(2.8) denotes C₁₋₄-alkyl or C₆₋₁₀-aryl;        -   R^(2.10) denotes NHR^(2.10.1) or a heterocyclic non-aromatic            C₃₋₁₀ ring, optionally substituted by C₁₋₄-alkyl; preferably            a heterocyclic, non-aromatic C₃₋₁₀ ring which may contain            one, two, or three heteroatoms, selected from among oxygen            and nitrogen, wherein R^(2.10.1) denotes H, cyclopropyl, or            C₁₋₆-alkyl, optionally substituted by O—C₁₋₄-alkyl; or    -   R² denotes C₆₋₁₀-aryl, optionally substituted by a group        selected from among phenyl and a heterocyclic C₃₋₁₀ ring,        optionally substituted by C₁₋₄-alkyl, COOR^(2.8), CN, halogen,        OR^(2.8), NHCOMe, or oxo; or    -   R² denotes a heterocyclic, non-aromatic C₅₋₁₀ ring, optionally        substituted by a group selected from among benzyl or COR^(2.11);        -   R^(2.11) denotes a group selected from among C₃₋₇-cycloalkyl            and a heterocyclic aromatic or non-aromatic C₅₋₁₀ ring,            optionally substituted by one or more C₁₋₄-alkyl, optionally            substituted by OH, OMe, NH₂, or NHCOO-^(t)Bu; or    -   R² denotes a group selected from among C₂₋₆-alkenyl, indanyl,        1,2,3,4-tetrahydronaphthalyl, or        8-methyl-8-azabicyclo[3.2.1]octane; or    -   NR¹R² together denotes a heterocyclic, non-aromatic C₃₋₁₀ ring        which is optionally substituted by methyl;    -   R³ denotes a group selected from among a heterocyclic, aromatic        C₅₋₁₀ ring, C₆₋₁₀-aryl-C₁₋₆-alkylene,        C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, and CH₂-benzo[1,3]dioxolyl; or    -   R³ denotes phenyl, optionally substituted by one or more groups        selected from among C₁₋₄-alkyl, C₁₋₄-alkylene-NR^(3.1)R^(3.2),        CN, COOR^(3.1), CONR^(3.1)R^(3.2), CF₃, OR^(3.1), halogen,        NHCOR^(3.1), NO₂, SO₂NR^(3.1)R^(3.2), C₁₋₄-alkylene-NHCOR^(3.1);        -   R^(3.1) denotes H or C₁₋₄-alkyl;        -   R^(3.2) denotes H or C₁₋₄-alkyl; or    -   R³ denotes a group of formula 1b        -   R^(3.3) denotes a group selected from among a heterocyclic,            non-aromatic C₃₋₁₀ ring, optionally substituted by one or            more groups selected from among C₁₋₄-alkyl, oxo,            COR^(3.3.1), COR^(3.3.2), C₁₋₄-alkylene-R^(3.3.2),            CH₂COpyrrolidine, heterocyclic C₃₋₁₀ ring, wherein a sulfur            atom optionally contained in the heterocyclic C₃₋₁₀ ring may            optionally be in the form of the oxide or dioxide;            -   R^(3.3.1) denotes C₁₋₄-alkyl;            -   R^(3.3.2) denotes NH₂, NH(C₁₋₄-alkyl), or                N(C₁₋₄-alkyl)₂; or        -   R^(3.3) denotes a fused, bicyclic heteroring or heterocyclic            spiroring; or    -   R³ denotes a group of formula 1c        -   A denotes a bond or C₁₋₄-alkyl, optionally substituted by            oxo or NMe₂;        -   R^(3.4) denotes H or C₁₋₄-alkyl;        -   R^(3.5) denotes a group selected from among a heterocyclic            C₃₋₁₀ ring or a bicyclic ring, optionally substituted by one            or more groups selected independently of one another from            among oxo, C₁₋₄-alkyl, OH, C₆₋₁₀-aryl, heterocyclic,            aromatic C₅₋₁₀ ring, C₁₋₄-alkylene-R^(3.5.1),            O—C₁₋₄-alkylene-R^(3.5.1), NH—C₁₋₄-alkylene-R^(3.5.1);            -   R^(3.5.1) denotes a group selected from among                C₆₋₁₀-aryl, heterocyclic C₃₋₁₀ ring, optionally                substituted by C₁₋₄-alkyl; or    -   R³ denotes a group of formula 1d        -   D denotes C₂₋₄-alkynyl;        -   R^(3.6) denotes pyridinyl; or    -   R³ denotes a group COR^(3.7), COCH₂R^(3.8), CONHR^(3.8),        SO₂R^(3.8), or a group of formula 1e        -   R^(3.7) denotes H, C₁₋₄-alkyl, or C₆₋₁₀-aryl;        -   R^(3.8) denotes C₁₋₄-alkyl, C₃₋₇-cycloalkyl, or a group            selected from among C₆₋₁₀-aryl, heterocyclic C₅₋₁₀ ring, and            a bicyclic ring, optionally substituted by one or more            groups selected from among C₁₋₄-alkyl, halogen,            NR^(3.8.1)R^(3.8.2), C₆₋₁₀-aryl, and heterocyclic,            non-aromatic C₃₋₁₀ ring, wherein        -   R^(3.8.1) denotes H or C₁₋₄-alkyl; and        -   R^(3.8.2) denotes H or C₁₋₄-alkyl;    -   R⁴ denotes H, methyl, or oxo;    -   R⁵ denotes H or methyl;    -   R⁶ denotes H or methyl;    -   R⁷ denotes H, methyl, phenyl, or OH;    -   R⁸ denotes H, methyl, phenyl, or OH; or    -   R⁷ and R⁸ together form oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Preferred compounds of formula 1 above are those wherein

-   -   X denotes O, S, SO, or SO₂; preferably S, SO, or SO₂;    -   R¹ denotes H, methyl, ethyl, or propyl; preferably H and propyl    -   R² denotes H or C₁₋₆-alkyl, which may optionally be substituted        by one or more groups selected from among CF₃, CN, OH, NMe₂,        OMe, COOH, and CONMe₂, or    -   R² denotes C₁₋₆-alkyl, which may optionally be substituted by        one or more groups selected from cyclopropyl, cyclopentyl,        cyclohexyl, phenyl, pyrrolidinyl, imidazolidinyl, pyrazolyl,        imidazolyl, and pyridinyl, which may optionally be substituted        by methyl or oxo; or    -   R² denotes C₃₋₇-cycloalkyl, which may optionally be substituted        by a group selected from among methyl, OR^(2.3),CH₂OR^(2.3),        COOH, CONR^(2.3)R^(2.4), CONH-^(t)Bu, O-benzyl, NR^(2.3)R^(2.4),        and NHCOR^(2.5), wherein        -   R^(2.3) denotes H, methyl, or        -   R^(2.4) denotes H or methyl;        -   R^(2.5) denotes CH₂C(CH₃)₃, CH₂C(CH₃)₂(CH₂OH), cyclopentyl,            tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, or            isoxazolyl, or    -   R² denotes a group of formula 1a        -   Y denotes C₁₋₄-alkylene, optionally substituted by one or            two R^(2.7)        -   R^(2.7) each independently of one another denote C₁₋₄-alkyl,            COOH, CONH₂; or R^(2.7) together with one or two carbon            atoms of Y forms a carbocyclic ring with 3 carbon atoms, or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by        one or more groups selected independently of one another from        among methyl, tert-butyl, CN, F, Cl, Br, OH, OMe, OEt, O-phenyl,        COOH, COOMe, COR^(2.10), NHCOMe, and morpholinyl-C₁₋₄-alkylene,        wherein R^(2.10) denotes NH₂, NHMe, NH-^(i)Pr, NH-cyclopropyl,        NHCH₂CH₂OMe, or a heterocyclic, non-aromatic C₃₋₁₀ ring, which        may contain one, two, or three heteroatoms selected from among        oxygen and nitrogen; preferably NH2, NHMe, NH-^(i)Pr,        NH-cyclopropyl, NHCH₂CH₂OMe, morpholinyl, or methylpiperazinyl;        or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by a        group selected from among phenyl and a heterocyclic C₃₋₁₀ ring,        which may optionally be substituted by one or more groups        selected from among methyl, tert-butyl, COOH, COOMe, CN, F, Cl,        Br, OH, OMe, OEt, and NHCOMe, oxo; preferably phenyl,        imidazolidinyl, optionally substituted by methyl or oxo; or    -   R² denotes a heterocyclic non-aromatic C₃₋₁₀ ring which may        optionally be substituted by a group selected from among benzyl        and COR^(2.11), wherein R^(2.1) denotes a group selected from        among cyclopentyl, tetrahydrofuranyl, furan, pyridyl, pyrrolyl,        pyrazolyl, imidazolyl, which may optionally be substituted by        one or two methyl groups, or by one or more groups selected from        among CH₂C(CH₃)₃, C(CH₃)₂(CH₂OH), CH₂OMe, C(CH₃)₂NH₂, and        C(CH₃)₂NHCOO-^(i)Bu; or    -   R² denotes a group selected from among C₂₋₆-alkenyl, indanyl,        1,2,3,4-tetrahydronaphthalyl, and        8-methyl-8-azabicyclo[3.2.1]octane; or    -   NR¹R² denotes a group selected from among pyrrolidinyl,        piperidinyl, piperazinyl, and morpholinyl, which may optionally        be substituted by methyl;    -   R³ denotes H or a group selected from among pyridinyl,        pyrimidinyl, benzyl, and CH₂-benzo[1,3]dioxolyl; or    -   R³ denotes phenyl, which may optionally be substituted by one,        two, or three groups selected from among methyl, CH₂NH₂, CN,        COOH, CONH₂, CF₃, OH, F, Cl, Br, OMe, NHCOMe, NR^(3.1)COR^(3.2),        CONR^(3.1)R^(3.2), NO₂, SONMe₂, and CH₂NHCOMe; wherein        -   R^(3.1) denotes H, C₁₋₆-alkyl, or an optionally bridged,            mono- or bicyclic C₃₋₁₀ heterocycle; and        -   R^(3.2) denotes H or C₁₋₆-alkyl; or    -   R³ denotes a group of formula 1b        -   R^(3.3) denotes a group selected from among piperidinyl,            piperazinyl, azepanyl, which may optionally be substituted            by one or more groups selected independently of one another            from among methyl, oxo, COCH₃, CONH₂, CH₂NEt₂, CH₂CH₂NMe₂,            CH₂COpyrrolidine, pyridinyl, isothiazolidinyl-1,1-dioxide,            and thiazolidinyl-1,1-dioxide, or        -   R^(3.3) denotes a group of formula        -   R³ denotes a group of formula 1c        -   A denotes a bond or C₁₋₄-alkyl, which may optionally be            substituted by oxo or NMe₂,        -   R^(3.4) denotes H or methyl;        -   R^(3.5) denotes a group selected from among pyrrolidinyl,            piperidinyl, piperazinyl, morpholinyl, cyclohexyl,            imidazolyl, pyrazolyl, phenyl, pyridinyl, benzimidazolyl,            imidazolidin-2-one, pyrrolidin-2-one, pyrrolidin-3-one,            tetrahydrothiophene-1,1-dioxide, and            1-azabicyclo[2.2.2]octane, which may optionally be            substituted by one or more groups selected independently of            one another from among methyl, ethyl, OH, phenyl, pyridinyl,            pyrazolyl, pyrrolidinyl, (CH₂)_(o)—R^(3.5.1),            O—(CH₂)_(o)—R^(3.5.1), and NH—(CH₂)_(o)—R^(3.5.1), wherein:            o denotes 0, 1, or 2, and R^(3.5.1) denotes a group selected            from among phenyl, pyrrolidinyl, piperidinyl, and            imidazolidin-2-one, which may optionally be substituted by            methyl; or    -   R³ denotes a group of formula 1d        -   denotes C₂₋₄-alkynyl;        -   R^(3.6) denotes pyridinyl; or    -   R³ denotes a group COR^(3.7), COCH₂R^(3.8), CONHR^(3.8),        SO₂R^(3.8), or a group of formula 1e        -   R^(3.7) denotes H, methyl, or phenyl;        -   R^(3.8) denotes a group selected from among isopropyl,            cyclopropyl, cyclopentyl, cyclohexyl, pyrrolidinyl,            pyrrolidin-2-one, furanyl, and azabicyclo[2.2.2]octanyl or a            group selected from among piperidinyl, pyrazolyl,            imidazolyl, isoxazolyl, pyridinyl, phenyl, benzyl, which may            optionally be substituted by one or more groups selected            from among methyl, chlorine, NH₂, NMe₂, phenyl, and            morpholinyl;    -   R⁴ denotes H, methyl, or oxo;    -   R⁵ denotes H or methyl;    -   R⁶ denotes H or methyl;    -   R⁷ denotes H, methyl, or OH; preferably H or methyl;    -   R⁸ denotes H, methyl, or OH; preferably H or methyl; or    -   R⁷ and R⁸ together form oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Preferred compounds of formula 1 above are those wherein:

-   -   X denotes S, SO, or SO₂;    -   R¹ denotes H, methyl, or ethyl;    -   R² denotes a group selected from H, ethyl, n-propyl, isopropyl,        n-butyl, n-pentyl, n-hexyl,    -   NR¹R² denotes a group selected from among    -   R³ denotes a group selected from among    -   R⁴ denotes H, methyl, or oxo;    -   R⁵ denotes H or methyl;    -   R⁶ denotes H or methyl;    -   R⁷ denotes H or methyl; and    -   R⁸ denotes H or methyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined and R¹denotes H; and the pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein R¹,R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined and X denotesSO; and the pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein R¹,R³, R⁴, and X are as hereinbefore defined and R⁵, R⁶, R⁷, and R⁸ denoteH; and the pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein R¹,R², R³, R⁵, R⁶, R⁷, R⁸, and X are as hereinbefore defined and R⁴ denotesH; and the pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein R¹,R³, R⁴, R⁵ , R⁷, R⁸, and X are as hereinbefore defined and wherein

-   -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by        one or more groups selected independently of one another from        among C₁₋₆-alkyl, C₁₋₄-haloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        CN, halogen, OR^(2.8), COOR^(2.8), COR^(2.10), NR^(2.8)R^(2.9),        NHCOR^(2.8), SR^(2.8), SOR^(2.8), SO₂R^(2.8), and        SO₂NR^(2.8)R^(2.9), or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by        one or more groups selected from among C₆₋₁₀-aryl-C₁₋₆-alkylene,        C5-lo-heteroaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl, and a heterocyclic        C₃₋₁₀ ring, which may optionally be substituted by a group        selected from among C₁₋₆-alkyl, C₁₋₆-haloalkyl, COOR^(2.8), CN,        halogen, OR^(2.8), NHCOR^(2.8), oxo, a C₃₋₇-cycloalkyl-C₁₋₄        alkylene, a heterocycle-C₁₋₄ alkylene, and a        NR^(2.1)R^(2.2)—C₁₋₄-alkylene, wherein:        -   R^(2.8) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, a            NR^(2.1)R^(2.2)—C₁₋₄- alkylene, or C₆₋₁₀-aryl;        -   R^(2.9) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;        -   R^(2.10) denotes NHR^(2.10.1), C₁₋₆-alkylene-O—C₁₋₄-alkyl,            or a heterocyclic C₃₋₁₀ ring which may optionally be            substituted by C₁₋₄-alkyl, wherein R^(2.10.1) denotes H,            C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, or C₃₋₇-cycloalkyl;            or    -   R² denotes C₆₋₁₀-aryl, to which an aromatic or non-aromatic        C₃₋₁₀ heterocycle is fused; or    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by a        group selected from among C₆₋₁₀-aryl and a heterocyclic C₃₋₁₀        ring, which is optionally substituted by one or more groups        selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,        C₁₋₄-haloalkyl, CN, halogen, OR^(2.8), COOR^(2.8),        COR^(2.10)NR^(2.8)R^(2.9), NHCOR^(2.8), SR^(2.8), SOR^(2.8),        SO₂R² SO₂NR^(2.8)R^(2.9), and oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R² denotes C₆₋₁₀-aryl, optionally substituted by one or more        groups selected independently of one another from among        C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₄-haloalkyl, CN,        halogen, OR^(2.8), COOR^(2.8), COR^(2.10) NR^(2.8)R^(2.9),        NHCOR^(2.8), SR^(2.8), SOR^(2.8), SO₂R^(2.8), and        SO₂NR^(2.8)R^(2.9), wherein:        -   R^(2.8) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,            or C₆₋₁₀-aryl;        -   R^(2.9) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;        -   R^(2.10) denotes NHR^(2.10.1) C₁₋₆-alkylene-O—C₁₋₄-alkyl, or            a heterocyclic C₃₋₁₀ ring, optionally substituted by            C₁₋₄-alkyl, wherein R^(2.10.1) denotes H, C₁₋₆-alkyl,            C₂₋₆-alkenyl, C₂₋₆-alkynyl, or C₃₋₇-cycloalkyl; or    -   R² denotes C₆₋₁₀-aryl, optionally substituted by a group        selected from among C₆₋₁₀-aryl and a heterocyclic C₃₋₁₀ ring,        optionally substituted by C₁₋₆-alkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, C₁₋₄-haloalkyl, CN, halogen, OR^(2.8), COOR^(2.8),        COR^(2.10)NR^(2.8)R^(2.9), NHCOR^(2.8), SR^(2.8), SOR^(2.8),        SO₂R^(2.8), SO₂NR^(2.8) R^(2.9), and oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

R² denotes C₆₋₁₀-aryl, which may optionally be substituted by one ormore groups selected from among C₁₋₄-alkyl, CN, halogen, OR²R^(2.8),COOR²R^(2.8), COR^(2.10), and NHCOMe, wherein:

-   -   -   R^(2.8) denotes C₁₋₄-alkyl or C₆₋₁₀-aryl;        -   R^(2.10) denotes NHR^(2.10.1), morpholinyl, or            methylpiperazinyl, and R^(2.10.1) denotes H, cyclopropyl, or            C₁₋₄-alkyl, which may optionally be substituted by one or            more groups selected from O—C₁₋₄-alkyl, OH, or C₆₋₁₀-aryl;            or

    -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted by a        group selected from among phenyl and a heterocyclic C₃₋₁₀ ring,        which may optionally be substituted by C₁₋₄-alkyl, COOR^(2.8),        CN, halogen, OR^(2.8), NHCOMe, and oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein:

-   -   R² denotes C₆₋₁₀-aryl, optionally substituted by one or more        groups selected independently of one another from among methyl,        tert-butyl, CN, F, Cl, Br, OH, OMe, OEt, O-phenyl, COOH, COOMe,        COR^(2.10), and NHCOMe        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined and R²denotes

and the pharmacologically acceptable salts, diastereomers, enantiomers,racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined and R²denotes H; and the pharmacologically acceptable salts, diastereomers,enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein:

-   -   R² denotes a group selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,        and C₂₋₆-alkynyl; preferably C₁₋₆-alkyl; particularly preferably        propyl, which may optionally be substituted by a group selected        from among C₁₋₆-haloalkyl, CN, OR^(2.1), NR^(2.1)R^(2.2),        COOR^(2.1), NHCOR^(2.1), SR^(2.1), SOR^(2.1), SO₂R^(2.1), and        CONR^(2.1)R^(2.2), preferably by a group selected from among        C₁₋₄-haloalkyl, CN, OR^(2.1), NR^(2.1)R^(2.2), COOR², and        CONR^(2.1)R^(2.2) or which may optionally be substituted by a        group selected from among C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a        heterocyclic, aromatic C₃₋₁₀ ring, which may in turn optionally        be substituted by C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, or        oxo; preferably by methyl or oxo, wherein:        -   R^(2.1) denotes H or is selected from among C₁₋₄-alkyl,            C₂₋₆-alkenyl, or C₂₋₆-alkynyl, preferably H or C₁₋₄-alkyl;            and        -   R^(2.2) denotes H or is selected from among C₁₋₄-alkyl,            C₂₋₆-alkenyl, or C₂₋₆-alkynyl, preferably H or C₁₋₄-alkyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R² denotes a group selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,        and C₂₋₆-alkynyl; preferably C₁₋₆-alkyl; particularly preferably        propyl, optionally substituted by a group selected from among        C₁₋₆-haloalkyl, CN, OR^(2.1,) NR^(2.1)R^(2.2), NHCOR^(2.1),        SR^(2.1), SOR^(2.1), SO^(2.1), SO₂NR^(2.1)R^(2.2), COOR^(2.1),        and CONR^(2.1)R^(2.2) or optionally substituted by a group        selected from among C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a        heterocyclic C₃₋₁₀ ring, optionally substituted by C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, or oxo, wherein:        -   R^(2.1) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl; and        -   R^(2.2) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R² denotes C₁₋₆-alkyl, which may optionally be substituted by a        group selected from among C₁₋₄-haloalkyl, CN, OR^(2.1),        NR^(2.1)R^(2.2), COOR^(2.1), and CONR^(2.1)R^(2.2) or which may        optionally be substituted by a group selected from among        C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a heterocyclic, aromatic C₃₋₁₀        ring, which may in turn optionally be substituted by methyl or        oxo, wherein:        -   R^(2.1) denotes H or C₁₋₄-alkyl; and        -   R^(2.2) denotes H or C₁₋₄-alkyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R² denotes C₁₋₆-alkyl; preferably propyl; particularly        preferably n-propyl, optionally substituted by a group selected        from among CF₃, CN, OH, NMe₂, OMe, COOH, and CONMe₂ or        optionally substituted by a group selected from among        cyclopropyl, cyclopentyl, cyclohexyl, phenyl, pyrrolidinyl,        imidazolidinyl, pyrazolyl, imidazolyl, and pyridinyl, optionally        substituted by methyl or oxo;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein

-   -   R² denotes a group selected from among ethyl, n-propyl,        isopropyl, n-butyl, n-pentyl, n-hexyl,        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein

-   -   R² denotes C₆₋₁₀-aryl, which may optionally be substituted in        the meta position by one or more groups selected independently        of one another from among C₁₋₄-alkyl, CN, halogen, OR^(2.8),        COOR^(2.8), COR^(2.10), and NHCOMe, wherein:        -   R^(2.8) denotes C₁₋₄-alkyl or C₆₋₁₀-aryl; and        -   R^(2.10) denotes NHR^(2.10.1), morpholinyl, or            methylpiperazinyl, and R^(2.10.1) denotes H, cyclopropyl, or            C₁₋₄-alkyl, wherein the C₁₋₄-alkyl may optionally be            substituted by one or more groups selected from among            C₁₋₄-alkyl, OH, and C₆₋₁₀-aryl; or    -   R² denotes NH(R^(2.10.1)) or cyclohexyl, or    -   NR¹R² denotes a heterocyclic C₅₋₆ ring selected from among        pyrrolidine and piperazine, which may optionally be substituted        by one or more groups selected from among C₁₋₄-alkyl, OH, and        C₁₋₄-alkanol,        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein

-   -   R³ denotes phenyl, which may optionally be substituted by one or        more groups selected from among C₁₋₆-alkyl, C₂₋₆-alkenyl,        C₂₋₆-alkynyl, C₁₋₄-haloalkyl, C₁₋₆-alkylene-NR^(3.1)R^(3.2), CN,        halogen, OR^(3.1), COOR^(3.1), CONR^(3.1)R^(3.2),        NR^(3.1)R^(3.2), NHCOR^(3.1), NO₂, SR^(3.1), SOR^(3.1),        SO₂R^(3.1), SO₂NR^(3.1)R^(3.2), and C₁₋₆-alkylene-NHCOR^(3.1),        wherein:        -   R^(3.1) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl; and        -   R^(3.2) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein:

-   -   R³ denotes phenyl, which may optionally be substituted in the        para position by a group selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₄-haloalkyl,        C₁₋₆-alkylene-NR^(3.1)R^(3.2), CN, halogen, OR^(3.1),        COOR^(3.1), CONR^(3.1)R^(3.2), NR^(3.1)R^(3.2), NHCOR^(3.1),        NO₂, SR^(3.1), SOR^(3.1), SO₂R^(3.1), SO₂NR^(3.1)R^(3.2), and        C₁₋₆-alkylene-NHCOR^(3.1), wherein:        -   R^(3.1) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;        -   R^(3.2) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or            C₂₋₆-alkynyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R³ denotes phenyl, which may optionally be substituted by one or        more groups selected from among C₁₋₄-alkyl,        C₁₋₄-alkylene-NR^(3.1)R^(3.2), CN, COOR^(3.1),        CONR^(3.1)R^(3.2), CF₃, OR^(3.1), halogen, NHCOR^(3.1), NO₂,        SO₂NR^(3.1)R^(3.2), and C₁₋₄-alkylene-NHCOR^(3.1), wherein:        -   R^(3.1) denotes H or C₁₋₄-alkyl; and        -   R^(3.2) denotes H or C₁₋₄-alkyl;            and the pharmacologically acceptable salts, diastereomers,            enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and

-   -   R³ denotes phenyl, which may optionally be substituted by one,        two, or three groups selected from among methyl, CH₂NH₂, CN,        COOH, CONH₂, CF₃, OH, F, Cl, Br, OMe, NHCOMe, NO₂, SONMe₂, and        CH₂NHCOMe;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and R³denotes a group of formula 1b

-   -   R^(3.3) denotes a heterocyclic C₃₋₁₀ ring which may optionally        be substituted by one or more groups selected from among        C₁₋₆-alkyl, oxo, COR^(3.3.1), COR^(3.3.2),        C₁₋₆-alkylene-R^(3.3.2), CH₂COpyrrolidine, and a heterocyclic        C₃₋₁₀ ring, wherein a sulfur atom optionally contained in the        heterocyclic C₃₋₁₀ ring may optionally also be present as the        oxide or dioxide, wherein:        -   R^(3.3.1) denotes C₁₋₆-alkyl; and        -   R^(3.3.2) denotes NH₂, NH(C₁₋₆-alkyl), or N(C₁₋₆-alkyl)₂; or    -   R^(3.3) denotes a bicyclic ring or a heterocyclic spiro ring;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and whereinR³ denotes a group of formula 1b

-   -   R^(3.3) denotes a group selected from among piperidinyl,        piperazinyl, and azepanyl, which may optionally be substituted        by one or more groups selected from among methyl, oxo, COCH₃,        CONH₂, CH₂NEt₂, CH₂CH₂NMe₂, CH₂COpyrrolidine, pyridinyl,        isothiazolidinyl-1,1-dioxide, and thiazolidinyl-1,1-dioxide;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and whereinR³ denotes a group of formula 1c

-   -   A denotes a bond or C₁₋₆-alkyl, which may optionally be        substituted by oxo or NMe₂;    -   R^(3.4) denotes H or C₁₋₆-alkyl;    -   R^(3.5) denotes a group selected from among C₁₋₆-alkyl, which        may optionally be substituted by a group selected from among        C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a C₅₋₁₀ heterocycle, which may        also optionally be substituted in each case by one or more        groups selected from among halogen, OH, oxo, C₁₋₆-alkyl,        O—C₁₋₆-alkyl, C₁₋₆-haloalkyl, a heterocyclic C₃₋₁₀ ring, and a        bicyclic ring, while these groups may each optionally be        substituted by one or more groups selected from among oxo,        C₁₋₆-alkyl, OH, C₆₋₁₀-aryl, a heterocyclic ring,        C₁₋₆-alkylene-R^(3.5), O—C₁₋₆-alkylene-R^(3.5) , and        NH—C₁₋₆-alkylene-R^(3.5.1), or    -   R^(3.5) denotes a group selected from among heterocyclic or        bicyclic ring, optionally substituted by one or more groups        selected independently of one another from among oxo,        C₁₋₆-alkyl, OH, aryl, a heterocyclic ring,        C₁₋₆-alkylene-R^(3.5.1), O—C₁₋₆-alkylene-R^(3.5.1),        NH—C₁₋₆-alkylene-R^(3.5.1), wherein R^(3.5.1) denotes a group        selected from among C₆₋₁₀-aryl, and heterocyclic C₃₋₁₀ ring        which may optionally be substituted by C₁₋₆-alkyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and whereinR³ denotes a group of formula 1c

-   -   A denotes a bond or C₁₋₄-alkyl, optionally substituted by oxo or        NMe₂;    -   R^(3.4) denotes H or methyl;    -   R^(3.5) denotes a group selected from among pyrrolidinyl,        piperidinyl, piperazinyl, morpholinyl, cyclohexyl, imidazolyl,        pyrazolyl, phenyl, pyridinyl, benzimidazolyl,        imidazolidin-2-one, pyrrolidin-2-one, pyrrolidin-3-one,        1-azabicyclo[2.2.2]octane, optionally substituted by one or more        groups selected independently of one another from among methyl,        ethyl, OH, phenyl, pyridinyl, pyrazolyl, pyrrolidinyl,        (CH₂)_(o)—R^(3.5.1), O—(CH₂)_(o)—R^(3.5.1),        NH—(CH₂)_(o)—R^(3.5.1), wherein: o denotes 0, 1, or 2, and        R^(3.5.1) denotes a group selected from among phenyl,        pyrrolidinyl, piperidinyl, and imidazolidin-2-one, optionally        substituted by methyl,        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁵, R⁶, R⁷, and R⁸ are as hereinbefore defined, and whereinR³ denotes a group of formula 1d

-   -   is D denotes C₂₋₄-alkynyl;    -   R^(3.6) denotes pyridinyl;        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

Particularly preferred are the above compounds of formula 1, wherein X,R¹, R², R⁴, R⁶, R⁷, and R⁸ are as hereinbefore defined, and wherein R³denotes a group of formula 1

-   -   R^(3.7) denotes H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, or        C₁₋₆-haloalkyl;    -   R^(3.8) denotes H or a group selected from among C₁₋₆-alkyl,        C₂₋₆-alkenyl; C₂₋₆-alkynyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,        C₆₋₁₀-aryl, a heterocyclic C₃₋₁₀ ring, and a bicyclic ring which        is optionally substituted by one or more groups selected from        among halogen, C₁₋₆-alkyl, OH, C₁₋₆-haloalkyl, and O—C₁₋₆-alkyl,        and the pharmacologically acceptable salts, diastereomers,        enantiomers, racemates, hydrates, or solvates thereof.

The present invention also relates to the following intermediateproducts for synthesizing the compounds according to the invention:

-   -   compounds according to formula VIII according to preparation        method B in Scheme 1,    -   compounds according to formula IV and V according to preparation        method A in Scheme 1,    -   compounds according to formula I in Scheme 1,    -   compounds according to formula IV, VI, VII, and VIII in Scheme        2,    -   compounds according to formula V, VII, and VIII in Scheme 3,    -   compounds according to formula V, VII, and IX in Scheme 4,    -   compounds according to formula V, VI, VII, VIII, and IX in        Scheme 5,    -   compounds according to formula V, VII, VIII, and IX in Scheme 6,    -   compounds according to formula V, VII, VIII, XI, and XII in        Scheme 7,    -   compounds according to formula I and II in Scheme 8,    -   compounds according to formula II and III in Scheme 9,    -   compounds according to formula V, VI, VIII, and X in Scheme 10,    -   compounds according to formula III and V in Scheme 11,    -   compounds according to formula III and V in Scheme 12,    -   compounds according to formula II, III, IV, and V in Scheme 13,        and    -   compounds according to formula IV, V, VII, VIII, IX, and X in        Scheme 14,        wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and X have the meanings        defined hereinbefore and wherein R⁹, R¹⁰, R¹¹, R¹² in each case        independently of one another denote a group selected from among        H, halogen, C₁₋₆-alkyl, C₁₋₆-haloalkyl, C₆₋₁₀-aryl,        C₃₋₇-cycloalkyl, aromatic or non-aromatic C₃₋₁₀ heterocycle,        C₆₋₁₀-aryl-C₁₋₆-alkylene, C₃₋₇-cycloalkyl-C₁₋₆-alkylene, and        C₃₋₁₀ heterocycle-C₁₋₆-alkylene, which may optionally be        substituted by one or more groups selected from among OH, oxo,        C₁₋₆-alkyl, phenyl C₃₋₇-cycloalkyl, C₃₋₇ heterocycle, and        halogen, and wherein R¹³ is selected from among OH, halogen,        O—C₁₋₆-alkyl, C₁₋₆-alkyl, phenyl, C₃₋₇-cycloalkyl, and C₃₋₇        heterocycle.

Preferred objects of the present invention are the followingintermediate products for synthesizing the compounds according to theinvention:

-   -   compounds according to formula I in Scheme 1,    -   compounds according to formula VI, VII, and VIII in Scheme 2,    -   compounds according to formula VII and VIII in Scheme 3,    -   compounds according to formula VII and IX in Scheme 4,    -   compounds according to formula VI, VII, VIII, and IX in Scheme        5,    -   compounds according to formula VII, VIII, and IX in Scheme 6,    -   compounds according to formula VII, VIII, XI, and XII in Scheme        7,    -   compounds according to formula I and II in Scheme 8,    -   compounds according to formula II and III in Scheme 9,    -   compounds according to formula X in Scheme 10,    -   compounds according to formula III and V in Scheme 11,    -   compounds according to formula III and V in Scheme 12,    -   compounds according to formula II, III, IV, and V in Scheme 13,        and    -   compounds according to formula VII, VIII, IX, and X in Scheme        14.

TERMS AND DEFINITIONS USED

Unless otherwise stated, all the substituents are independent of oneanother. If, for example, there are a plurality of C₁₋₆-alkyl groups assubstituents in one group, in the case of three substituents C₁₋₆-alkyl,one may represent methyl, one n-propyl, and one tert-butyl.

Within the scope of this application, in the definition of possiblesubstituents, these may also be represented in the form of a structuralformula. An asterisk (*) in the structural formula of the substituent isto be understood as being the linking point to the rest of the molecule.Moreover, the atom of the substituent which follows the linking point isreferred to as the atom in position number 1. Thus, for example, thegroups N-piperidinyl (I), 4-piperidinyl (II), 2-tolyl (III), 3-tolyl(IV), and 4-tolyl (V) are shown as follows:

If there is no asterisk (*) in the structural formula of thesubstituent, each hydrogen atom may be removed from the substituent andthe valency thus freed may act as a binding site to the rest of amolecule. Thus, for example, VI may represent 2-tolyl, 3-tolyl, 4-tolyl,and benzyl

By the term “C₁₋₆-alkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkyl” are meant branched andunbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to4 carbon atoms are preferred. Examples include: methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl, or hexyl. The following abbreviations mayoptionally also be used for the abovementioned groups: Me, Et, n-Pr,i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless stated otherwise, the definitionspropyl, butyl, pentyl, and hexyl include all the possible isomeric formsof the groups in question. Thus, for example, propyl includes n-propyland isopropyl, butyl includes isobutyl, sec-butyl and tert-butyl etc.

By the term “C₁₋₆-alkylene” (including those which are part of othergroups) are meant branched and unbranched alkylene groups with 1 to 6carbon atoms and by the term “C₁₋₄-alkylene” are meant branched andunbranched alkylene groups with 1 to 4 carbon atoms. Preferred arealkylene groups with 1 to 4 carbon atoms. Examples include: methylene,ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene,1,1-dimethylethylene, 1,2-dimethylethylene, pentylene,1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene,1,3-dimethylpropylene, or hexylene. Unless stated otherwise, thedefinitions propylene, butylene, pentylene, and hexylene include all thepossible isomeric forms of the groups in question with the same numberof carbons. Thus, for example, propyl also includes 1-methylethylene andbutylene includes 1-methylpropylene, 1,1-dimethylethylene,1,2-dimethylethylene.

If the carbon chain is substituted by a group which together with one ortwo carbon atoms of the alkylene chain forms a carbocyclic ring with 3,5, or 6 carbon atoms, the following examples of rings are also included:

By the term “C₂₋₆-alkenyl” (including those which are part of othergroups) are meant branched and unbranched alkenyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenyl” are meant branched andunbranched alkenyl groups with 2 to 4 carbon atoms, provided that theyhave at least one double bond. Alkenyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethenyl or vinyl, propenyl, butenyl,pentenyl, or hexenyl. Unless stated otherwise, the definitions propenyl,butenyl, pentenyl, and hexenyl include all the possible isomeric formsof the groups in question. Thus, for example, propenyl includes1-propenyl and 2-propenyl, butenyl includes 1-, 2-, and 3-butenyl,1-methyl-1-propenyl, 1-methyl-2-propenyl, etc.

By the term “C₂₋₆-alkenylene” (including those which are part of othergroups) are meant branched and unbranched alkenylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkenylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Preferred arealkenylene groups with 2 to 4 carbon atoms. Examples include:ethenylene, propenylene, 1-methylethenylene, butenylene,1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene,pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene,1,2-dimethylpropenylene, 1,3-dimethylpropenylene, or hexenylene. Unlessstated otherwise, the definitions propenylene, butenylene, pentenylene,and hexenylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propenylalso includes 1-methylethenylene and butenylene includes1-methylpropenylene, 1,l-dimethylethenylene, and 1,2-dimethylethenylene.

By the term “C₂₋₆-alkynyl” (including those which are part of othergroups) are meant branched and unbranched alkynyl groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynyl” are meant branched andunbranched alkynyl groups with 2 to 4 carbon atoms, provided that theyhave at least one triple bond. Alkynyl groups with 2 to 4 carbon atomsare preferred. Examples include: ethynyl, propynyl, butynyl, pentynyl,or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl,pentynyl, and hexynyl include all the possible isomeric forms of thegroups in question. Thus, for example, propynyl includes 1-propynyl and2-propynyl, butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl,1-methyl-2-propynyl etc.

By the term “C₂₋₆-alkynylene” (including those which are part of othergroups) are meant branched and unbranched alkynylene groups with 2 to 6carbon atoms and by the term “C₂₋₄-alkynylene” are meant branched andunbranched alkylene groups with 2 to 4 carbon atoms. Preferred arealkynylene groups with 2 to 4 carbon atoms. Examples include:ethynylene, propynylene, 1-methylethynylene, butynylene,1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene,pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene,1,2-dimethylpropynylene, 1,3-dimethylpropynylene, or hexynylene. Unlessstated otherwise, the definitions propynylene, butynylene, pentynylene,and hexynylene include all the possible isomeric forms of the groups inquestion with the same number of carbons. Thus, for example, propynylalso includes 1-methylethynylene and butynylene includes1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.

By the term “aryl” (including those which are part of other groups) aremeant aromatic ring systems with 6 or 10 carbon atoms. Examples include:phenyl or naphthyl, the preferred aryl group being phenyl. Unlessotherwise stated, the aromatic groups may be substituted by one or moregroups selected from among methyl, ethyl, isopropyl, tert-butyl,hydroxy, fluorine, chlorine, bromine, and iodine.

By the term “aryl-C₁₋₆-alkylene” (including those which are part ofother groups) are meant branched and unbranched alkylene groups with 1to 6 carbon atoms, which are substituted by an aromatic ring system with6 or 10 carbon atoms. Examples include: benzyl, 1- or 2-phenylethyl, or1- or 2-naphthylethyl. Unless otherwise stated, the aromatic groups maybe substituted by one or more groups selected from among methyl, ethyl,isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

By the term “heteroaryl-C₁₋₆-alkylene” (including those which are partof other groups) are meant, even though they are already included under“aryl-C₁₋₆-alkylene”, branched and unbranched alkylene groups with 1 to6 carbon atoms, which are substituted by a heteroaryl.

A heteroaryl of this kind includes five- or six-membered heterocyclicaromatic groups or 5-10-membered, bicyclic heteroaryl rings which maycontain one, two, or three heteroatoms selected from among oxygen,sulfur, and nitrogen, and contain so many conjugated double bonds thatan aromatic system is formed. The following are examples of five- orsix-membered heterocyclic aromatic groups:

Unless otherwise stated, these heteroaryls may be substituted by one ormore groups selected from among methyl, ethyl, isopropyl, tert-butyl,hydroxy, fluorine, chlorine, bromine, and iodine. The following areexamples of heteroaryl-C₁₋₆-alkylenes:

By the term “C₁₋₆-haloalkyl” (including those which are part of othergroups) are meant branched and unbranched alkyl groups with 1 to 6carbon atoms, which are substituted by one or more halogen atoms. By theterm “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1to 4 carbon atoms, which are substituted by one or more halogen atoms.Alkyl groups with 1 to 4 carbon atoms are preferred. Examples include:CF₃, CHF₂, CH₂F, and CH₂CF₃.

By the term “C₃₋₇-cycloalkyl” (including those which are part of othergroups) are meant cyclic alkyl groups with 3 to 7 carbon atoms. Examplesinclude: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl. Unless otherwise stated, the cyclic alkyl groups may besubstituted by one or more groups selected from among methyl, ethyl,isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.

By the term “heterocyclic rings” or also “heterocycles” are meant five-,six-, or seven-membered, saturated or unsaturated heterocyclic ringswhich may contain one, two, or three heteroatoms, selected from amongoxygen, sulfur, and nitrogen, while the ring may be linked to themolecule through a carbon atom or through a nitrogen atom, if there isone. Although included by the term “heterocyclic rings” or“heterocycles”, the term “heterocyclic non-aromatic rings” refers tofive-, six-, or seven-membered unsaturated rings. Examples include:

Although included by the term “heterocyclic rings” or “heterocycles”,the term “heterocyclic aromatic rings” or “heteroaryl” refers to five-or six-membered heterocyclic aromatic groups or 5-10-membered, bicyclicheteroaryl rings which may contain one, two, or three heteroatoms,selected from among oxygen, sulfur, and nitrogen, and contain so manyconjugated double bonds that an aromatic system is formed. Examples offive- or six-membered heterocyclic aromatic groups include:

Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) maybe provided with a keto group. Examples include:

By the term “bicyclic rings” are meant eight-, nine-, or ten-memberedbicyclic rings which may optionally contain one or more heteroatoms,selected from among oxygen, sulfur, and nitrogen. The ring may be linkedto the molecule through a carbon atom of the ring or through a nitrogenatom of the ring, if there is one. Examples include:

Although included by the term “bicyclic rings”, the term “fused bicyclicrings” denotes bicyclic rings wherein the bridge separating the ringsdenotes a direct single bond. The following are examples of a fused,bicyclic ring:

Although included by the term “bicyclic rings”, the term “fused bicyclicheterorings” denotes bicyclic 5-10 membered heterorings which containone, two, or three heteroatoms, selected from among oxygen, sulfur, andnitrogen, and wherein the bridge separating the rings denotes a directsingle bond. Examples include pyrrolizine, indole, indolizine,isoindole, indazole, purine, quinoline, isoquinoline, benzimidazole,benzofuran, benzopyran, benzothiazole, benzothiazole, benzoisothiazole,pyridopyrimidine, pteridine, pyrimidopyrimidine,

By the term “heterocyclic spirorings” (spiro) are meant 5-10 membered,spirocyclic rings which may optionally contain one, two, or threeheteroatoms, selected from among oxygen, sulfur, and nitrogen, while thering may be linked to the molecule through a carbon atom or through anitrogen atom, if there is one. Unless otherwise mentioned, aspirocyclic ring may be provided with an oxo, methyl, or ethyl group.Examples include:

“Halogen” within the scope of the present invention denotes fluorine,chlorine, bromine, or iodine. Unless stated to the contrary, fluorine,chlorine, and bromine are regarded as preferred halogens.

By the term “ambient temperature” is meant normal room temperature.

Compounds of general formula 1 may have acid groups, mainly carboxylgroups, and/or basic groups such as, e.g., amino functions. Compounds ofgeneral formula 1 may therefore be present as internal salts, as saltswith pharmaceutically useable inorganic acids such as, for example,hydrochloric acid, sulfuric acid, phosphoric acid, sulfonic acid, ororganic acids (such as, for example, maleic acid, fumaric acid, citricacid, tartaric acid, or acetic acid) or as salts with pharmaceuticallyuseable bases such as alkali or alkaline earth metal hydroxides orcarbonates, zinc, or ammonium hydroxides or organic amines such as e.g.,diethylamine, triethylamine, or triethanolamine, inter alia.

As mentioned hereinbefore, the compounds of formula 1 may be convertedinto the salts thereof, particularly for pharmaceutical use, into thephysiologically and pharmacologically acceptable salts thereof. Thesesalts may on the one hand be in the form of the physiologically andpharmacologically acceptable acid addition salts of the compounds offormula 1 with inorganic or organic acids. On the other hand, if R ishydrogen, the compound of formula 1 may also be converted by reactionwith inorganic bases into physiologically and pharmacologicallyacceptable salts with alkali or alkaline earth metal cations as counterion. The acid addition salts may be prepared, for example, usinghydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, or maleic acid. It is also possible touse mixtures of the abovementioned acids. The alkali and alkaline earthmetal salts of the compound of formula I are preferably prepared usingthe alkali and alkaline earth metal hydroxides and hydrides thereof, ofwhich the hydroxides and hydrides of the alkaline earth metals,particularly of sodium and potassium, are preferred and sodium andpotassium hydroxide are particularly preferred.

If desired, the compounds of general formula (1) may be converted intothe salts thereof, particularly, for pharmaceutical use, into thepharmacologically acceptable acid addition salts with an inorganic ororganic acid. Suitable acids include, for example, succinic acid,hydrobromic acid, acetic acid, fumaric acid, maleic acid,methanesulfonic acid, lactic acid, phosphoric acid, hydrochloric acid,sulfuric acid, tartaric acid, or citric acid. It is also possible to usemixtures of the abovementioned acids.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids such as, for example, acid additionsalts with hydrohalic acids, for example, hydrochloric or hydrobromicacid or organic acids such as, for example, oxalic, fumaric, diglycolic,or methanesulfonic acid.

The compounds according to the invention may optionally occur asracemates, but they may also be obtained as pure enantiomers, i.e., inthe (R) or (S) form. Preferred compounds are those which occur asracemates or as the (S) form.

The invention relates to the compounds in question, optionally in theform of the individual optical isomers, mixtures of the individualenantiomers or racemates, in the form of the tautomers as well as in theform of the free bases or the corresponding acid addition salts withpharmacologically acceptable acids such as, for example, acid additionsalts with hydrohalic acids, for example, hydrochloric or hydrobromicacid or organic acids, such as, for example, oxalic, fumaric,diglycolic, or methanesulfonic acid.

METHODS OF SYNTHESIS AND EXAMPLES

Synthesis of[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl]propylamineby Synthesis Method A (1) (Scheme 1)

2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (IV):6.4 g (39 mmol) of N-phenylpiperazine (III) is placed in 2.2 mL ofglacial acetic acid, heated to 125° C., then 3.2 g (15 mmol) of2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is added,and the mixture is heated to 175° C. After 1.5 hours, the resultingsolid is stirred with water, suction filtered, washed with ethanol, anddried. 4.3 g product (91%) is obtained as a powder.

4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V): 4.3 g (13.7 mmol) of2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (IV)and 25 mL of phosphorus oxychloride are combined and stirred for 5 hoursat 120° C. Excess phosphorus oxychloride is concentrated by evaporation,the residue is combined with ice water and dichloromethane. The organicphase is separated off and evaporated to dryness. The residue istriturated with water, suction filtered, and dried. 5.6 g of the product(100%) is obtained as a powder.

[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl]propylamine(I) (Example 27): 0.83 g (2.5 mmol) of4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V) is combined with 8.3 mL of n-propylamine, reacted for 0.2 hours at130° C. in the microwave. Then the reaction mixture is added to waterand extracted with dichloromethane. The organic phase is concentrated byevaporation, the residue is crystallized. The aqueous phase is extractedwith ethyl acetate, the organic phase evaporated to dryness. The solidsare combined and stirred with methanol. 0.68 g of the product (76%) isobtained as a powder.

Synthesis of[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine-4-yl]propylamineby Synthesis Method B (Scheme 1)

6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (VI): 3.5 g (16.33 mmol) of2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (II) is placed in70 mL of 1N hydrochloric acid, reacted for 0.75 hours at 150° C. in themicrowave (14×0.250 g in 5 mL of hydrochloric acid in each case). Thenthe reaction mixture is left to stand for 7 hours at ambienttemperature. It is suction filtered, washed with water, and dried. 2.6 gof the product VI (95%) is obtained as a powder.

2.4-dichlorothieno[3,2-d]pyrimidine (VII)-2.4 g (14.1 mmol) of6,7-dihydrothieno[3,2-d]pyrimidine-2,4-diol (VI) is suspended in 14 mLof phosphorus oxychloride, combined with 4.5 mL (28.2 mmol) ofdiethylaniline and stirred for 22 hours at 80° C. After cooling toambient temperature, the reaction mixture is added to ice water, theprecipitate formed is suction filtered and washed with water. Theprecipitate is dissolved in dichloromethane, any water present isseparated off using a phase separator. The organic phase is evaporatedto dryness. 2.5 g of the product VII (85%) is obtained.

(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VII): 10.4g (50.2 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (VII), 8.2 mL (100mmol) of N-propylamine, and 17.5 mL (100 mmol) ofN-ethyldiisopropylamine are placed in 100 mL of tetrahydrofuran andstirred for 20 hours at ambient temperature. The suspension is filtered,the filtrate is concentrated by evaporation. The residue is combinedwith 100 mL of water and treated in the ultrasound bath. Solid substanceis suction filtered, dried, and stirred with 50 mL of petroleum ether.10.0 g of the product VIII (86%) is obtained as a powder.

[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]propylamine(Example 27) (1): 9.7 g (42.3 mmol) of2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VIII) and25.7 mL (169.2 mmol) of 1-phenylpiperazine (III) are placed in 200 mL ofdioxane (carried out in 10 batches), then reacted for 1 hour at 160° C.in the microwave. The reaction mixture is concentrated by evaporation,the residue is combined with 250 mL of water. Then the mixture issuction filtered, washed with water, and dried. The residue is stirredwith acetonitrile, then recrystallized from isopropanol. 8.3 g of theproduct (I) (55%) is obtained as a powder (m.p. 121° C.). ¹H NMR (400MHz, DMSO): 7.22 (2H, t); 6.97 (2H, d); 6.79 (1H, t); 6.43 (2H, t);3.81-3.69 (4H, m); 3.37-3.19 (4H, m); 3.19-3.09 (4H, m); 2.99 (2H, t);1.62-1.47 (2H, m); 0.87 (3H, t).

The following Examples are prepared by synthesis method A (Scheme 1) asdescribed above (in each case only the last step of the synthesis isdescribed, namely the reaction of V with an amine to form product I).

cyclohexyl-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(Example 16) (I): 0.300 g (0.90 mmol) of4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V) is placed in 4 mL of cyclohexylamine, then reacted for 0.1 hours at130° C. in the microwave. Then the reaction mixture is concentrated byevaporation, the residue is stirred with water and suction filtered.0.120 g of product I (34%) is obtained as a powder. ¹H NMR (400 MHz,DMSO): 7.22 (2H, t); 6.97 (2H, d); 6.79 (1H, t); 6.08 (1H, d); 3.93-3.81(1H, m); 3.80-3.69 (4H, m); 3.22 (2H, t); 3.18-3.11 (4H, m); 2.98 (2H,t); 1.92-1.79 (2H, m); 1.79-1.66 (2H, m); 1.66-1.55 (1H, m); 1.37-1.21(4H, m); 1.18-1.04 (1H, m).

(3-chlorophenyl)-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(Example 10) (1): 0.320 g (0.96 mmol) of4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V), 1.0 mL (9.5 mmol) of 3-chlorophenylamine, and 0.33 mL (1.92 mmol)of diisopropylethylamine are combined and the mixture is reacted for 0.5hours at 130° C. in the microwave. Then the reaction mixture is combinedwith ethyl acetate and acidically extracted. The organic phase is driedand evaporated to dryness. The residue is combined with acetonitrile,water, and trifluoroacetic acid. The phase containing the product I ispurified by chromatography through an RP column by HPLC (column:Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1%formic acid (A), water+0.13% formic acid (B)). gradient: minutes %eluant A % eluant B 0 10 90 4.9 10 90 27 100 0 32 100 0 32.5 10 90 37.510 90

Corresponding fractions are combined and freeze-dried. 0.10.1 g of theproduct is obtained as a powder. ¹H NMR (400 MHz, DMSO): 8.63 (1H, s);7.87 (1H, t); 7.60 (1H, dd); 7.31 (1H, t); 7.26-7.20 (2H, m); 7.05-7.01(1H, m); 6.99 (2H, d); 7.80 (1H; t); 3.81-3.76 (4H, m); 3.22-3.15 (4H,m); 3.10 (2H, t).

(3-methoxyphenyl)-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(Example 11) (1): 0.320 g (0.96 mmol) of4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V), 1.5 mL (13.1 mmol) of 3-methoxyphenylamine, and 0.33 mL (1.92 mmol)of diisopropylethylamine are combined, and reacted for 0.5 hours at 130°C. in the microwave. Then the reaction mixture is purified bychromatography using HPLC through an RP column (column: Microsorb,RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid(A), water+0.13% formic acid (B)). gradient: minutes % eluant A % eluantB 0 10 90 4.9 10 90 27 100 0 32 100 0 32.5 10 90 37.5 10 90

0.095 g of the product (23%) is obtained as a powder (m.p. 133° C.-135°C.). ¹H NMR (400 MHz, DMSO): 8.37 (1H, s); 7.36 (1H, t); 7.26-7.14 (4H,m); 6.98 (2H, d); 6.80 (1H, t); 6.57 (1H, dd); 3.82-3.76 (4H, m); 3.75(3H, s); 3.32-3.24 (2H, m); 3.21-3.15 (4H, m); 3.09 (2H, t).

Phenyl-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(Example 18) (1): 0.300 g (0.90 mmol) of4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine(V) and 3 mL of phenylamine are combined, then reacted for 0.3 hours at130° C. in the microwave. Then the reaction mixture is combined withwater and extracted with ethyl acetate. The organic phase is dried andevaporated to dryness. The residue is triturated with diethyl ether andsuction filtered. 0.18 g of product I (51%) is obtained (m.p. 174°C.-175° C.). ¹H-NMR (400 MHz, DMSO): 8.59 (1H, s); 7.63 (2H, d); 7.31(2H, t); 7.22 (2H, t); 7.03 (1H, t); 6.99 (2H, d); 6.80 (1H, t);3.83-3.73 (4H, m); 3.31 (2H, t); 3.23 (4H, m); 3.12 (2H, t).

The following Examples are prepared by synthesis method B (Scheme 1) asdescribed above (in each case only the last step of the synthesis isdescribed (reaction of VIII with III to obtain produce I).

{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(1) (Example 37): 0.250 g (1.1 mmol) of2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VIII),0.700 g (3.6 mmol) of 1-(4-chlorophenyl)piperazine (III), and 0.400 mL(2.3 mmol) of diisopropylethylamine are placed in 4 mL of dioxane, thenreacted for 1.5 hours at 160° C. in the microwave. The reaction mixtureis combined with water while cooling with ice and treated in theultrasound bath. The precipitate formed is suction filtered, washed withwater and petroleum ether and dried. 0.300 g of product I (72%) isobtained as a powder. ¹H NMR (400 MHz, DMSO): 7.24 (2H, d); 6.98 (2H,d); 6.42 (1H, t); 3.79-3.70 (4H, m); 3.23 (2H, t); 3.19-3.11 (4H, m);2.98 (2H, t); 1.61-1.47 (2H, m); 0.87 (4, 3H).

{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(1) (Example 39): 0.400 g (1.7 mmol) of2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (VIII), 1.55g (8.7 mmol) of 1-(4-hydroxyphenyl)piperazine (III), and 0.610 mL (3.5mmol) of diisopropylethylamine are placed in 4 mL of dimethylformamide,reacted for 2 hours at 160° C. in the microwave. Then the reactionmixture is combined with water and extracted with dichloromethane. Theorganic phase is dried and evaporated to dryness. The residue ispurified by chromatography through a 10 g silica gel cartridge withpetroleum ether/ethyl acetate 1:1. 0.370 g of product I (57%) isobtained as a powder. ¹H NMR (400 MHz, DMSO): 8.80 (1H, s); 6.82 (2H,d); 6.66 (2H, d); 6.39 (1H, t); 3.76-3.69 (4H, m); 3.23 (2H, t);3.02-2.92 (6H, m); 1.60-1.48 (2H, m); 0.86 (3H, t).

((1R,2R)-2-benzyloxycyclopentyl)-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(chiral) (Example 112) (1): 0.450 g (1.2 mmol) of((1R,2R)-2-benzyloxycyclopentyl)(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine(chiral) (VIII) and 0.760 mL (5.0 mmol) of 1-phenylpiperazine (III) areplaced in 5 mL of dioxane, then reacted for 1 hour at 160° C. in themicrowave. The reaction mixture is concentrated by evaporation, and theresidue is combined with water and extracted with dichloromethane. Theorganic phase is separated off using a phase separator and evaporated todryness. The crude product I is purified by chromatography through a 100g silica gel cartridge with a solvent mixture of petroleum ether/ethylacetate 8/2. 0.540 g of the product (89%) is obtained (m.p. 100° C.-105°C.). ¹H NMR (400 MHz, DMSO): 7.36-7.18 (7H, m); 6.91 (2H, d); 6.79 (1H,t); 6.39 (1H, d); 4.59-4.40 (3H, m); 3.95-3.89 (1H, m); 3.79-3.69 (4H,m); 3.23 (2H, t); 3.11-3.03 (4H, m); 2.99 (2H, t); 2.11-2.00 (1H, m);1.93-1.79 (1H, m); 1.77-1.50 (4H, m).

Synthesis of4-[4-(4-cyclohexylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoicacid (According to Scheme 2)

ethyl4-[4-(4-cyclohexylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoate(VI): 2.1 g (7.8 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)cyclohexylamine (IV),3.1 g (13.2 mmol) of ethyl 4-piperazin-1-ylbenzoate (V), and 2.9 mL(16.5 mmol) of diisopropylethylamine are placed in 20 mL of dioxane,then the mixture is reacted for 4 hours at 1 60° C. in the microwave.The precipitated substance is suction filtered, the mother liquor isconcentrated by evaporation. The residue is extracted with water andethyl acetate, the combined organic phases are dried and evaporated todryness. The crude product is VI is crystallized from petroleumether/ethyl acetate 9:1. 2.3 g of the product (62%) is obtained.

4-[4-(4-cyclohexylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoicacid (VII) (Example 106): 2.3 g (4.8 mmol) of ethyl4-[4-(4-cyclohexylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoate(VI) and 26 mL (26 mmol) of sodium hydroxide is placed in 15 mL oftetrahydrofuran and 15 mL of methanol, and refluxed for 2 hours withstirring. Then the reaction mixture is concentrated by evaporation, theresidue is acidified with 2N hydrochloric acid. The precipitate formedis suction filtered, washed with water, and dried. 2.1 g of the productVII (100%) is obtained as a powder.

Standard Method for Synthesizing Amides: A solution of 0.01 mmol of theacid (VII) in 500 μL of dimethylformamide is combined with 1.388 μL(0.01 mmol) of triethylamine and 3.21 mg (0.01 mmol) ofO-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and shaken for 15 minutes at ambient temperature. To thisreaction mixture is added a solution of 0.01 mmol of the amine (amine A)in 500 μL dimethylformamide and the mixture is shaken for 12 hours atambient temperature. Then the reaction mixture is evaporated to drynessand purified by preparative HPLC (this yields product VIII).

The following Examples may be prepared analogously to the method ofsynthesis set out above (according to Scheme 2) (in each case only thereactions of the acids VII with the amines A to yield product VIII aredescribed):

4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]-N-(4-pyrrolidin-1-ylmethylbenzyl)benzamide(VIII) (Example 90): 0.350 g (0.9 mmol) of4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoicacid (VII) is placed in 8 mL of dimethylsulfoxide, 0.15 mL (0.9 mmol) ofdiisopropylethylamine, and 0.340 g (0.9 mmol) ofO-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) is added. The mixture is stirred for 0.1hours at ambient temperature, then 0.170 g (0.9 mmol) of4-pyrrolidin-1-ylmethylbenzylamine (amine A) is added and a further 0.9mmol of diisopropylethylamine is added. The reaction mixture is stirredfor 3 hours at ambient temperature, then suction filtered through Aloxand washed with dimethylsulfoxide. The mother liquor is concentrated byevaporation, the residue is cooled in the ice bath and combined withwater. Any precipitate formed is suction filtered and dried. Then it istreated with approx. 50 mL of petroleum ether in the ultrasound bath,and the precipitate is then suction filtered. 0.374 g of product VIII(75%) is obtained (m.p. 157-158° C.). ¹H NMR (400 MHz, DMSO): 8.71 (1H,t); 7.79 (2H, d); 7.23 (4H, s); 6.99 (2H, d); 6.43 (1H, t); 4.43 (2H,d); 3.79-3.71 (4H, m); 3.52 (2H, s); 3.23 (2H, t); 2.99 (2H, t);2.44-2.34 (4H, m); 1.72-1.63 (4H, m); 1.61-1.48 (2H, m); 0.87 (3H, t).

N-(1-methylpiperidin-4-yl)-4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzamide(VIII) (Example 87): 0.500 g (1.3 mmol) of4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoicacid (VII) is placed in 12 mL of dimethylsulfoxide, 0.716 g (1.9 mmol)of O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) in 6 mL of dimethylsulfoxide is added. Themixture is stirred for 1 hour at ambient temperature. Then 0.143 g (1.3mmol) of 1-methylpiperidin-4-ylamine (amine A) in 6 mL ofdimethylsulfoxide is added, followed by another 2.5 mmol ofdiisopropylethylamine. The reaction mixture is stirred for 16 hours atambient temperature, then suction filtered through Alox. The Alox iswashed with dimethylsulfoxide. The mother liquor is evaporated todryness. The residue is stirred with water, suction filtered, and dried.0.470 g of product VIII (76%) is obtained as a powder (m.p. 229-233°C.). ¹H NMR (400 MHz, DMSO): 7.90 (1H, d); 7.75 (2H, d); 6.97 (2H, d);6.43 (1H, 20 d); 3.82-3.66 (5H, m); 3.23 (2H, t); 2.99 (2H, t);2.80-2.70 (2H, m); 2.15 (3H, s); 1.92 (2H, t); 1.77-1.68 (2H, m);1.64-1.49 (4H, m); 0.87 (3H, t).

Synthesis of3-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzoicacid (Scheme 3) (in each case only the reactions of V with VI and withthe amine A to yield the product VIII are described)

3-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl[benzoicacid (VIII) (Example 66) 0.900 g (3.9 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (V) and 1.5g (4.7 mmol) of 3-piperazin-1-yl]benzoic acid triflate (VI) are placedin 20 mL of dioxane, and 5 mL (36.7 mmol) of diisopropylethylamine(amine A) are added. The suspension is stirred for 24 hours at 180° C.in a pressurised glass container, then concentrated by evaporation. Theresidue is dissolved in acetonitrile and water, then purified by HPLCthrough an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant:water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroaceticacid (B)). gradient: minutes % eluant A % eluant B 0 90 10 2 90 10 11.50 100 13 0 100 13.5 90 10

Corresponding fractions are combined and freeze-dried. 0.43 g of productVIII (27%) is obtained.

Synthesis of4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzonitrile(IX) (Scheme 4) (Only the Reactions of V with VI to VII and of VII andVIII to IX are Described)

(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine(VII): 1.0 g (4.4 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (V) and 1.9g (21.8 mmol) of piperazine (VI) are placed in 10 mL of dioxane, thenreacted for 0.7 hours at 150° C. in the microwave. Then the reactionmixture is extracted with water and ethyl acetate, and the organic phaseis dried and evaporated to dryness. The residue is triturated withpetroleum ether and suction filtered. 0.97 g of product VII (80%) isobtained as a powder.

4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]benzonitrile(IX) (Example 76): 0.150 g (0.5 mmol) of(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine(VII), 0.082 g (0.45 mmol) of 4-bromobenzonitrile (VIII), 0.011 g (0.05mmol) of palladium acetate, 0.041 g (0.07 mmol) of Xantphos, and 0.204 g(0.6 mmol) of cesium carbonate are placed in 1 mL of toluene, thenstirred for 24 hours at 80° C. Then the reaction mixture is combinedwith water and extracted with ethyl acetate. The organic phase is washedwith water, dried, and evaporated to dryness. The residue is purified bychromatography through an RP column using HPLC (column: Microsorb,RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid(A), water+0.13% formic acid (B). gradient: minutes % eluant A % eluantB 0 10 90 4.9 10 90 27 100 0 32 100 0 32.5 10 90 37.5 10 90

Corresponding fractions are combined and freeze-dried. 0.08 g of productIX (47%) is obtained as a powder. ¹H NMR (400 MHz, DMSO): 7.59 (2H, d);7.04 (2H, d); 6.44 (1H, t); 3.78-3.71 (4H, m); 3.43-3.36 (4H, m); 3.23(2H, t); 2.99 (2H, t); 1.60-1.49 (2H, m); 0.86 (3H, t).

{2-[4-(4-nitrophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(IX) (Example 71): 0.100 g (0.358 mmol) of(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine(VII) (cf method explained previously), 0.038 mL (0.358 mmol) of1-fluoro-4-nitrobenzene (VIII), and 0.148 g (1.07 mmol) of potassiumcarbonate are placed in 4 mL of tetrahydrofuran, then stirred for 16hours at ambient temperature and 8 hours at 65° C. and left to stand fora further 16 hours at ambient temperature. Then the solution is combinedwith water and extracted with ethyl acetate. The organic phase is driedand evaporated to dryness. The residue is combined with water andacetonitrile, whereupon a precipitate forms. This is suction filtered,washed, and dried. 0.023 g of product IX (16%) is obtained as a powder.¹H NMR (400 MHz, DMSO): 8.07 (2H, d); 7.04 (2H, d); 6.49-6.43 (1H, m);3.81-3.73 (4H, m); 3.58-3.50 (4H, m); 3.24 (2H, t); 2.99 (2H, t);1.61-1.49 (2H, m); 0.87 (3H, t).

Standard Methods for the Synthesis of Amides, Ureas, and Sulfonamidesfrom(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine(Scheme 5)

Standard Method for the Synthesis of Amides (VIII): see above.

Standard Method for the Synthesis of Sulfonamides (IX): A solution of0.063 mmol of the amine (VI) in 1 mL of dichloromethane is combined with30 μL diisopropylamine and 0.065 mmol of sulfonic acid chloride,dissolved in 1 mL of dichloromethane, and stirred for 1 hour at ambienttemperature. Then the reaction mixture is evaporated to dryness andpurified by preparative HPLC.

Standard Method for the Synthesis of Ureas (VII): A solution of 0.063mmol of the amine (VI) in 1 mL of tetrahydrofuran is combined with 30 μLof diisopropylamine and 0.065 mmol of isocyanate, dissolved in 1 mL oftetrahydrofuran, and stirred for 1 hour at ambient temperature. Then thereaction mixture is evaporated to dryness and purified by preparativeHPLC.

Standard conditions for preparative HPLC purification: column: XTerra,MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A),acetonitrile+0.1% trifluoroacetic acid (B). gradient: minutes % eluant A% eluant B 0 90 10 2 90 10 11.5 0 100 13 0 100 13.5 90 10

Corresponding fractions are combined and freeze-dried. The followingExamples are prepared by the same method of synthesis according toScheme 5:

4-(4-cyclohexylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazine-1-carboxylicacid-phenylamide (VII) (Example 102): 0.330 g (1.0 mmol) ofcyclohexyl-(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine(VI) and 0.115 mL (1.0 mmol) of phenyl isocyanate are placed in 12.5 mLof tetrahydrofuran, then stirred for 1 hour at ambient temperature. Thenthe reaction mixture is concentrated by evaporation. The residue isstirred with water, suction filtered, washed with water and petroleumether, then dried. The crude product is purified by chromatographythrough a 25 g silica gel cartridge with a solvent mixture of petroleumether/ethyl acetate 1/1. 0.240 g of product VII (53%) is obtained as apowder (m.p. 207-210° C.). ¹H NMR (400 MHz, DMSO): 8.51 (1H, s); 7.47(2H, d); 7.23 (2H, t); 6.92 (1H, t); 6.11 (1H, d); 3.91-3.78 (1H, m);3.69-3.59 (4H, m); 3.53-3.44 (4H, m); 3.22 (2H, t); 2.98 (2H, t);1.92-1.78 (2H, m); 1.79-1.67 (2H, m); 1.65-1.56 (1H, m); 1.37-1.21 (4H,m); 1.18-1.04 (1H, m).

Synthesis ofN-{4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenyl}isonicotinamide(IX) (According to Scheme 6)

{2-[4-(4-bromophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(VII): 1.0 g (4.4 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (V), 4.2 g(17.4 mmol) of 1-(4-bromophenyl)piperazine (VI), and 2.0 mL (11.5 mmol)of diisopropylethylamine are placed in 12 mL of dioxane and reacted for2.5 hours at 160° C. in the microwave. Then the reaction mixture iscombined with water and dichloromethane and extracted. The organic phaseis washed with water, dried, and evaporated to dryness. The residue isfiltered through silica gel with petroleum ether/ethyl acetate (8/2).Corresponding fractions were concentrated by evaporation. 1.9 g ofproduct VII (100%) is obtained.

{2-[4-(4-iodophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(VIII): 1.55 g (3.6 mmol) of{2-[4-(4-bromophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(VII), 1.1 g (7.2 mmol) of sodium iodide, and 0.036 g (0.19 mmol) ofcopper iodide are taken, and under an argon atmosphere 0.060 mL (0.38mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine and 7 mL ofanhydrous/degassed dioxane are added. The reaction mixture is heated for1.5 hours at 140° C. in the microwave, then diluted with dioxane, andsuction filtered through Alox. The dioxane was concentrated byevaporation. 1.70 g of product VIII (81%) is obtained as a powder.

N-{4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenyl}isonicotinamide(IX) (Example 237): 0.170 g (0.4 mmol) of{2-[4-(4-iodophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamine(VIII), 0.054 g (0.4 mmol) of isonicotinamide, 0.100 g (0.7 mmol) ofpotassium carbonate, and 0.004 g (0.02 mmol) of copper iodide are taken,and under an argon atmosphere 1 mL of anhydrous/degassed dioxane and0.006 mL (0.04 mmol) of trans-N,N-dimethyl-1,2-cyclohexanediamine areadded. The reaction mixture is reacted for 2 hours at 140° C. in themicrowave, then filtered through silica gel with petroleum ether/ethylacetate (1/1) and then ethyl acetate/methanol (8/2), and concentrated byevaporation. The residue is purified by chromatography (column:Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1%formic acid (A), water+0.13% formic acid (B)). gradient: minutes %eluant A % eluant B 0 10 90 4.9 10 90 10.5 30 70 20 30 70 21 100 0 25100 0 26.5 10 90 31.5 10 90

0.08 g of product IX (50%) is obtained as a powder. ¹H NMR (400 MHz,DMSO): 10.29 (1H, s); 8.77 (2H, d); 7.85 (2H, d); 7.64 (2H, d); 7.01(2H, d); 3.86-3.75 (4H, m); 3.23-3.07 (6H, m); 1.64-1.50 (2H, m); 0.88(3H, t).

Synthesis of Isoxazole-5-carboxylicacid-{(1S,2S)-2-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]cyclopentyl}amidetriflate (XI) (chiral) (According to Scheme 7)

tert-butyl[(1S,2S)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopentyl]carbamate(V) (chiral): 0.600 g (2.9 mmol) of2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (III), 0.580 g (2.9mmol) of tert-butyl (2-aminocyclopentyl)carbamate (IV), and 2.5 mL (14.5mmol) of diisopropylethylamine are placed in 30 mL of tetrahydrofuran,the mixture is stirred for 2 hours at ambient temperature and 72 hoursat 80° C. The reaction mixture is concentrated by evaporation andfurther reacted in the crude state.

tert-butyl{(1S,2S)-2-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]cyclopentyl}carbamate(VII) (chiral): 1.08 g (2.9 mmol) of tert-butyl[(1S,2S)-2-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)cyclopentyl]carbamate(V) (chiral) and 9.9 mmol of 1-phenylpiperazine (VI) are placed in 14 mLof dioxane, then heated to 160° C. for 2.3 hours. The reaction mixtureis concentrated by evaporation, the residue is then purified by HPLCthrough an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant:water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroaceticacid (B)). gradient: minutes % eluant A % eluant B 0 90 10 2 90 10 11.50 100 13 0 100 13.5 90 10

Corresponding fractions are combined and freeze-dried. 0.97 g of productVII (67%) is obtained.

(1S,2S)-N-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamineditriflate (VIII) (chiral): 0.960 g (1.9 mmol) of tert-butyl{(1S,2S)-2-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]cyclopentyl}carbamate(VII) (chiral) is dissolved in 40 mL of 25% trifluoroacetic acid indichloromethane and the mixture is stirred for 1 hour at ambienttemperature. Then the reaction mixture is concentrated by evaporation,the residue is combined with acetonitrile and water, and freeze-dried.1.2 g of product VIII (100%) is obtained as a powder.

isoxazole-5-carboxylicacid-{(1S,2S)-2-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]cyclopentyl}amidetriflate (chiral) (XI) (Example 277): 0.004 g (0.03 mmol) ofisoxazole-5-carboxylic acid (IX), 0.012 g (0.03 mmol) ofO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU), and 0.017 mL (0.10 mmol) of diisopropylethylamine are placed in1 mL of dimethylformamide, stirred for 0.1 hours at ambient temperature.Then 0.020 g (0.03 mmol) ofN-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamineditriflate (VIII) (chiral) in 1 mL of dimethylformamide are added. Themixture is shaken for 1 hour at ambient temperature. Then the reactionmixture is purified directly by HPLC through an RP column (column:XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid(A), acetonitrile+0.1% trifluoroacetic acid (B)). gradient: minute %eluant A % eluant B 0 90 10 2 90 10 11.5 0 100 13 0 100 13.5 90 10

Corresponding fractions are combined and freeze-dried. 0.003 g ofproduct XI (18%) is obtained.

Synthesis of(1S,2S)-N-(1-methyl-1H-pyrrol-2-ylmethyl)-N′-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diaminetriflate (chiral) (Example 310) (XII) (According to Scheme 7)

0.015 g (0.02 mmol) ofN-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamineditriflate (VIII) (chiral), 0.015 mL (0.14 mmol) of1-methyl-1H-pyrrole-2-carbaldehyde (X), 0.005 mL (0.09 mmol) of glacialacetic acid, and molecular sieve are placed in 2 mL ofdimethylformamide, and the mixture is stirred for 0.5 hours at ambienttemperature. Then first of all 0.070 g (0.23 mmol) of polyamine resin isadded, followed, after another 0.5 hours, by 0.030 g (0.14 mmol) ofsodium triacetoxyborohydride. The reaction mixture is shaken for 16hours at ambient temperature, filtered, and purified through anRP-column by HPLC (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant:water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroaceticacid (B)). Corresponding fractions are combined and lyophilized. 0.009 gof product XII (59%) is obtained. ¹H NMR (400 MHz, DMSO): 7.28-7.21 (2H,m); 7.00-6.95 (2H, m); 6.85-6.78 (2H, m); 6.21-6.18 (1H, m); 6.01-5.98(1H, m); 4.74-4.67 (1H, m); 4.19-4.12 (2H, m); 3.81-3.74 (4H, m);3.74-3.64 (1H, m); 3.59 (3H, t); 3.20-3.13 (4H, m); 3.11-3.03 (3H, m);2.19-2.03 (3H, m); 1.78-1.70 (4H, m); 1.67-1.54 (1H, m).

Synthesis ofcyclohexyl-[5-oxo-2-(4-phenylpiperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]amine(Example 297) (II) (According to Scheme 8)

0.120 g (0.3 mmol) ofcyclohexyl-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(I) is dissolved in 4 mL of acetic acid and 0.27 mL of 35% hydrogenperoxide solution is added. The mixture is stirred for 16 hours atambient temperature, then water is added. The reaction mixture is madebasic and extracted with ethyl acetate. The organic phase is dried andevaporated to dryness. The residue is purified by chromatography, theproduct is triturated with diethyl ether and suction filtered. 0.060 gof product II (48%) is obtained. ¹H NMR (400 MHz, DMSO): 7.40 (1H, d);7.23 (2H, t); 6.98 (21H, d); 6.80 (1H, t); 4.01-3.86 (5H, m); 3.48-3.37(1H, m); 3.28-3.13 (5H, m); 3.00-2.82 (2H, m); 1.92-1.81 (2H, m);1.80-1.69 (2H, m); 1.67-1.57 (1H, m); 1.43-1.21 (4H, m); 1.20-1.05 (1H,m).

The enantiomers were separated by analytical chiral HPLC (column:Chiralpak Diacel AD-H, 5 μM, 250*4.6 mm, flow rate: 1.0 mL/min, eluant:hexane/iPrOH (90/10)): Rt=14.6 min: enantiomer 1 (Example 367) [α_(D)²⁰+183 (CH₂Cl₂); Rt=16.4 min: enantiomer 2 (Example 368), [α_(D) ²⁰−189(CH₂Cl₂).

Synthesis of[5-oxo-2-(4-phenylpiperazin-1-yl-6,7-dihydro-5h-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]propylamine(example 298) (II) (According to Scheme 8)

0.240 g (0.68 mmol) of[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]propylamine(I) is dissolved in 5 mL of acetic acid, and 0.60 mL of 35% hydrogenperoxide solution are added while being cooled. The mixture is stirredfor 16. hours at ambient temperature, then water is added. The reactionmixture is made basic and extracted with dichloromethane. The organicphase is dried and evaporated to dryness. The residue is purified bychromatography, and the product is triturated with diethyl ether andsuction filtered. 0.130 g of product II (52%) is obtained. ¹H NMR (400MHz, DMSO): 7.69 (1H, t); 7.23 (2H, t); 6.98 (2H, d); 6.80 (1H, t);3.95-3.87 (4H, m); 3.49-3.19 (4H, m); 3.22-3.13 (4H, m); 3.01-2.82 (2H,m); 1.64-1.52 (2H, m); 0.88 (3H, t).

Synthesis of[5-oxo-2-(4-phenylpiperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]phenylamine(II) (Example 299) (According to Scheme 8)

0.190 g (0.49 mmol) ofphenyl-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]amine(I) is dissolved in 5 mL of acetic acid, and 0.43 mL of 35% hydrogenperoxide solution is added, with cooling. The mixture is stirred for 16hours at ambient temperature, then water is added. The reaction mixtureis made basic and extracted with dichloromethane. The organic phase isdried and evaporated to dryness. The residue is purified bychromatography, and the product is triturated with diethyl ether andsuction filtered. 0.100 g of product II (51%) is obtained. ¹H NMR (400MHz, DMSO): 9.54 (1H, s); 7.66 (2H, d); 7.35 (2H, t); 7.23 (2H, t); 7.09(1H, t); 6.98 (2H, d); 6.80 (1H, t); 3.96-3.85 (4H, m); 3.60-3.47 (1H,m); 3.32-3.15 (4H, m); 3.12-3.02 (1H, m); 3.01-2.92 (1H, m).

The following Examples are prepared as described above according toScheme 8:

(3-methoxyphenyl)-[5-oxo-2-(4-phenylpiperazin-1-yl)-6,7-dihydro-5h-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]amine(Example 302) (II according to Scheme 8): 0.072 g of product II (17%) isobtained as a powder (m.p. 217° C.-220° C.).

(3-chlorophenyl)-[5-oxo-2-(4-phenylpiperazin-1-yl)-6,7-dihydro-5H-5λ⁴-thieno[3,2-d]pyrimidin-4-yl]amine(Example 300) (II According to Scheme 8): 4.50 g of product II (73%) isobtained as a powder. (m.p. 230° C.-231° C.).

The enantiomers were separated by semipreparative chiral HPLC (column:Chiralpak Diacel IA, 5 μM, 200*25 mm, flow rate: 12 mL/min, eluant:TBME/EtOH (75/25)): Rt=16 min: Enantiomer 1 (Example 370), [α_(D)²⁰+221.3 (c 2.06, CH₂Cl₂).; Rt=19 min: Enantiomer 2 (Example 371),[α_(D) ²⁰−207.9 (c 2.24, CH₂Cl₂).

Synthesis of{2-[4-(4-chlorophenyl)piperazin-1-yl]-5,5-dioxo-6,7-dihydro-5h-5λ⁶-thieno[3,2-d]pyrimidin-4-yl}propylamine(Example 377) (III According to Scheme 9)

(2-chloro-5,5-dioxo-6,7-dihydro-5H-5λ⁶-thieno[3,2-d]pyrimidin-4-yl)propylamine(II): 0.805 g (3.50 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)propylamine (I) (seeScheme 1, preparation method B) is placed at ambient temperature in 14mL of trifluoroacetic acid, then combined with 0.82 mL (8.40 mmol) ofhydrogen peroxide (35% in water). The reaction mixture is stirred for 16hours at ambient temperature and 2 hours at 45° C. After the addition of0.5 equiv. hydrogen peroxide, the mixture is stirred for a further 0.5hours at 45° C., then stirred into ice water and made basic with ammoniasolution. Any precipitate formed is suction filtered, washed, and dried.0.720 g of product II (79%) is obtained as a powder.

{2-[4-(4-chlorophenyl)piperazin-1-yl]-5,5-dioxo-6,7-dihydro-5H-5λ⁶-thieno[3,2-d]pyrimidin-4-yl}propylamine(III): 0.262 g (1.00 mmol) of(2-chloro-5,5-dioxo-6,7-dihydro-5H-5k-thieno[3,2-d]pyrimidin-4-yl)propylamine(II) and 0.433 g (2.20 mmol) of 1-(4-chlorophenyl)piperazine are placedin 4.50 mL of dioxane, then heated to 150° C. in the microwave for 0.75hours. Then the reaction mixture is concentrated by evaporation, theresidue is treated with water. It is suction filtered, washed withwater, and dried. The product which is not yet clean is purified bychromatography (column: 10 g Chromabond SiOH cartridge, solvent:petroleum ether/ether 1:1). Corresponding fractions are combined andconcentrated by evaporation. 0.295 g of product III (70%) is obtained asa powder (m.p. 243° C.-245° C.).

The following Examples are prepared as described above according toScheme 9:

(3-chlorophenyl)-[5,5-dioxo-2-(4-phenylpiperazin-1-yl)-6,7-dihydro-5h-5λ⁶-thieno[3,2-d]pyrimidin-4-yl]amine(Example 375) (III according to Scheme 9): 0.163 g of product III (36%)is obtained as a powder (m.p. 234° C.).

(3-chlorophenyl)-{2-[4-(4-chlorophenyl)piperazin-1-yl]-5,5-dioxo-6,7-dihydro-5h-5λ⁶-thieno[3,2-d]pyrimidin-4-yl}amine(Example 376) (III according to Scheme 9): 0.173 g of product III (35%)is obtained as a powder (m.p. 246° C.).

Synthesis of(1-methyl-1H-pyrrol-2-yl)-{3-[2-(4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]piperidin-1-yl}methanone(X according to Scheme 10)

tert-butyl3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidine-1-carboxylate(V): 2.07 g (10.0 mmol) of2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine (III), 2.0 g (10.0 mmol)of tert-butyl 3-aminopiperidin-1-carboxylate (IV), and 3.4 mL (19.3mmol) of diisopropylethylamine are placed in 40 mL of tetrahydrofuran,then stirred for 40 hours at ambient temperature. Then the reactionmixture is suction filtered and the mother liquor is concentrated byevaporation. The residue is combined with water and extracted withdichloromethane. The organic phase is separated off using a phaseseparator and evaporated to dryness. The crude product is purified bychromatography through a Biotage silica gel cartridge 40M with petroleumether/ethyl acetate 9:1. 1.77 g of product V (48%) is obtained.

(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)piperidin-3-ylaminehydrochloride (VI): 1.77 g (4.8 mmol) of tert-butyl3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-carboxylate(V) is placed in 21.5 mL of a 4% hydrochloric acid solution in dioxane,and methanol is added. The solution is stirred for 0.5 hours at ambienttemperature, whereupon a precipitate is formed. This is suctionfiltered, washed with diethyl ether, and dried. 1.33 g of product (VI)(91%) is obtained.

(1-methyl-1H-pyrrol-2-yl)-[3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-yl]methanone(VIII): 0.462 g (3.7 mmol) of 1-methyl-1H-pyrrol-2-carboxylic acid(VII), 1.4 g (9.7 mmol) ofO-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate(HATU), and 0.640 mL (3.7 mmol) of diisopropylethylamine are placed in10 mL of dimethylsulfoxide, then stirred for 0.1 hours at ambienttemperature. 0.814 g (3.0 mmol) of(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)piperidin-3-ylaminehydrochloride (VI) and 3.7 mmol of diisopropylethylamine are added, thenthe mixture is stirred for 16 hours at ambient temperature. Then thereaction mixture is suction filtered through Alox, and the mother liquoris concentrated by evaporation. The residue is combined with 1 N sodiumhydroxide solution and extracted with dichloromethane. The organic phaseis separated off using a phase separator and evaporated to dryness. Thecrude product is purified by chromatography through a Biotage silica gelcartridge 40 s with petroleum ether/ethyl acetate 1:1. 0.970 g ofproduct VIII (85%) is obtained.

(1-methyl-1H-pyrrol-2-yl)-{3-[2-(4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino]piperidin-1-yl}methanone(X According to Scheme 10) (Example 230): 0.250 g (0.7 mmol) of(1-methyl-1H-pyrrol-2-yl)-[3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)piperidin-1-yl]methanone(VIII), 0.503 g (1.9 mmol) of 1-(4-chlorophenyl)piperazinedihydrochloride (IX), and 0.430 mL (2.5 mmol) of diisopropylethylamineare placed in 3.5 mL of dioxane, then reacted for 2.25 hours at 160° C.in the microwave. Then the reaction mixture is combined with water. Anyprecipitate formed is suction filtered, washed with water, and dried.0.167 g of product X (47%) is obtained as a beige powder. ¹H NMR (400MHz, DMSO): 7.25 (2H, d); 6.97 (2H, d); 6.84 (1H, t); 6.34-6.31 (1H, m),5.96 (1H, m); 4.46-4.34 (1H, m); 4.22-4.12 (1H, m); 4.04-4.92 (1H, m);3.73-3.64 (4H, m); 3.67 (3H, s); 3.24 (2H, t); 3.16-3.09 (4H, m);3.05-2.84 (4H, m); 1.97-1.88 (1H, m); 1.82-1.65 (2H, m); 1.55-1.43 (1H,m).

Synthesis of(3-{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino}piperidin-1-yl)morpholin-4-ylmethanonetriflate (Example 357) (III According to Scheme 11)

0.135 g (0.31 mmol) of{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}piperidin-3-ylamine(I) (see Scheme 1), 0.037 mL (0.31 mmol) of morpholine-4-carbonylchloride (II), 0.119 g (0.31 mmol) ofO-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.218 mL (1.25 mmol) ofdiisopropylethylamine are stirred in 6 mL of dimethylformamide for 18hours at ambient temperature. The reaction mixture is concentrated byevaporation, the residue is purified by chromatography (RP-HPLC). 0.040g of the product III (19%) is obtained after freeze-drying. ¹H NMR (400MHz, DMSO): 7.26 (2H, d); 7.00 (2H, d); 4.13-3.95 (m); 3.87-3.76 (m);3.68-3.60 (m); 3.59-3.43 (m); 3.43-3.34 (m); 3.31-3.09 (m); 2.88-2.77(m); 1.95-1.83 (1H, m); 1.78-1.60 (2H, m); 1.57-1.40 (m).

[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]-(1-pyridin-3-ylmethylpiperidin-3-yl)amineditriflate (Example 363) (V According to Scheme 11)

0.015 g (0.024 mmol) of{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}piperidin-3-ylamine(I) (see Scheme 1), 0.015 mL (0.158 mmol) of pyridine-3-aldehyde (IV),and 0.005 mL (0.087 mmol) of glacial acetic acid are stirred into 2 mLof DMF through a molecular sieve for 0.5 hour at ambient temperature.0.026 mg (0.123 mmol) of sodium triacetoxyborohydride is added and thereaction mixture is stirred for another 12 hours at ambient temperature.The reaction mixture is purified by chromatography (RP-HPLC). 0.009 g ofthe product V (50%) is obtained after freeze-drying. ¹H NMR (400 MHz,DMSO): 8.76-8.70 (1H, m); 8.65-8.58 (1H, m); 8.02-7.94 (1H, m);7.56-7.49 (1H, m); 7.33-7.21 (3H, m); 7.04-6.97 (2H, m); 6.89-6.81 (1H,m); 4.57-3.78 (m); 3.75-3.40 (m); 3.37-3.28 (2H, m); 3.20-3.03 (m);2.99-2.79 (1H, m); 2.78-2.59 (1H, m); 2.07-1.71 (3H, m); 1.69-1.52 (11H,m).

Synthesis of(4-methylpiperazin-1-yl)-(3-{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino}phenyl)methanone(V According to Scheme 12)

3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)benzoic acid(1): 0.200 g (0.93 mmol) of2,4-dichloro-6,7-dihydrothieno[3,2-d]pyrimidine, 0.127 g (0.93 mmol) of3-aminobenzoic acid, and 0.323 mL (1.85 mmol) of diisopropylethylamineare placed in 4 mL of tetrahydrofuran, stirred for 48 hours at ambienttemperature and 48 hours at 70° C. Then the reaction mixture is combinedwith water and acidified with 1N hydrochloric acid. The precipitateformed is suction filtered and dried. 0.110 g of product I (39%) isobtained.

(4-methylpiperazin-1-yl)-[3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)phenyl]methanone(III): 0.600 g (1.95 mmol) of3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)benzoic acid(I), 0.741 g (1.95 mmol) ofO-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.680 mL (3.90 mmol) ofdiisopropylethylamine are placed in 10 mL of dimethylsulfoxide, thenstirred for 0.5 hours at ambient temperature. 0.220 mL (1.95 mmol) ofmethylpiperazine (II) is added, then the mixture is stirred for 3 hoursat ambient temperature. Then the reaction mixture is concentrated byevaporation and the residue is combined with water. Any precipitateformed is suction filtered and dried. The crude product is purified bychromatography through a 50 g silica cartridge with ethylacetate/methanol 8:2. 0.250 g of product III (33%) is obtained.

(4-methylpiperazin-1-yl)-(3-{2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino}phenyl)methanone(V) (Example 236): 0.100 g (0.26 mmol) of(4-methylpiperazin-1-yl)-[3-(2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamino)phenyl]methanone(III), 0.207 g (0.77 mmol) of 1-(4-chlorophenyl)piperazine (IV), and0.180 mL (1.02 mmol) of diisopropylethylamine are placed in 3.5 mL ofdioxane, then reacted for a total of 2 hours at 160° C. in themicrowave. Then the reaction mixture is combined with water andextracted with ethyl acetate. The organic phase is dried and evaporatedto dryness. The residue is purified by chromatography using HPLC throughan RP column (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm,eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B))gradient: minutes % eluant A % eluant B 0 10 90 4.9 10 90 27 100 0 32100 0 32.5 10 90 37.5 10 90

Corresponding fractions are combined and freeze-dried. 0.014 g ofproduct V (10%) is obtained. ¹H NMR (400 MHz, DMSO): 8.60 (1H, s);7.76-7.70 (2H, m); 7.37 (1H, t); 7.25 (2H, d); 7.03 (1H, d); 6.98 (2H,d); 3.81-3.72 (5H, m); 3.72-3.37 (3H, m); 3.21-3.14 (4H, m); 3.10 (3H,t); 2.97-2.62 (4H, m).

Synthesis of4-[4-(4-amino-6,7-dihydrothieno[3,2-d[pyrimidin-2-yl)piperazin-1-yl]phenol(V According to Scheme 13)

2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol(II): 1.70 g (9.54 mmol) of 4-piperazin-1-ylphenol is placed in 0.55 mL(9.62 mmol) of glacial acetic acid and heated to 180° C. in the heatingblock. 0.800 g (3.73 mmol) of2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added,then the mixture is left to stand for 1.5 hours at 180° C. and 16 hoursat ambient temperature. Then the reaction mixture is combined with waterand treated in the ultrasound bath. The precipitate is suction filtered,washed, and dried. 1.1 g of product II is obtained as a powder.

4-[4-(4-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol(III): 1.11 g (3.36 mmol) of2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol(II) is placed in 5 mL of phosphorus oxychloride, then stirred for 4hours at 120° C. Excess phosphorus oxychloride is then distilled off andthe residue is combined with water. The precipitate formed is suctionfiltered, washed with plenty of water, and dried. 1.18 g of product IIIis obtained as a brown powder.

4-[4-(4-azido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol(IV): 1.18 g (2.75 mmol) of4-[4-(4-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol(III) is placed in 25 mL of dimethylformamide, and 1.20 g (18.46 mmol)of sodium azide is added. The reaction mixture is stirred for 4.5 hoursat 100° C. Then it is concentrated by evaporation, and the residue iscooled in the ice bath and combined with water. The precipitate formedis suction filtered, washed, and dried. 0.800 g of product IV isobtained and used further as a crude product.

4-[4-(4-amino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol(V) (Example 218): 0.800 g (1.80 mmol) of4-[4-(4-azido-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenol(IV) is placed in 10 mL of tetrahydrofuran and 0.500 g molecular sieveare added. 3.80 mL (3.80 mmol) of lithium aluminum hydride (1M solutionin tetrahydrofuran) is slowly added dropwise. The reaction mixture isstirred for 3 hours at ambient temperature. Then 0.55 mL of 1N sodiumhydroxide solution and 0.50 mL of water are added, the mixture is boiledfor 0.3 hours, then cooled again. It is filtered, and the filtrate isdried and evaporated to dryness. The residue is extracted with ethylacetate and 1 N hydrochloric acid, the aqueous phase is made basic andextracted with ethyl acetate. The organic phase is washed with water,dried, and evaporated to dryness. 0.280 g of product V is obtained as alight brown foam. ¹H NMR (400 MHz, DMSO): 8.80 (1H, s); 6.82 (2H, d);6.66 (2H, d); 6.26 (2H, s); 3.77-3.66 (4H, m); 3.21 (2H, t); 2.98 (2H,t); 2.98-2.90 (4H, m).

Synthesis of2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamine(V According to Scheme 13)

2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol(II): 1.9 g (9.66 mmol) of 1-(4-chlorophenyl)piperazine is placed in0.55 mL (9.62 mmol) of glacial acetic acid and heated to 180° C. in theheating block. 0.800 g (3.73 mmol) of2-ethylsulfanyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (I) is added,then the mixture is left to stand for 1.5 hours at 180° C. and 16 hoursat ambient temperature. Then the reaction mixture is combined with waterand treated in the ultrasound bath. The precipitate is suction filtered,washed, and dried. 1.25 g of product II is obtained and used further inthe crude state.

4-chloro-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine(III): 1.25 g (3.05 mmol) of2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol(II) is placed in 4.50 mL of phosphorus oxychloride, then stirred for 4hours is at 120° C. Then excess phosphorus oxychloride is distilled off,the residue is combined with water. The precipitate formed is suctionfiltered, washed with plenty of water, and dried, then stirred withmethanol. 0.960 g of product III (85%) is obtained.

4-azido-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine(IV): 0.950 g (2.59 mmol) of4-chloro-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine(III) is placed in 20 mL of dimethylformamide and 0.900 g (13.84 mmol)of sodium azide is added. The reaction mixture is stirred for 4 hours at100° C. It is then concentrated by evaporation, the residue is cooled inthe ice bath and combined with water. The precipitate formed is suctionfiltered, washed, and dried. 0.920 g of product IV (76%) is obtained andused further in the crude state.

2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-ylamine(Example 219) (V): 0.820 g (1.76 mmol) of4-azido-2-[4-(4-chlorophenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidine(IV) is placed in 10 mL of tetrahydrofuran and 3.80 mL (3.80 mmol) oflithium aluminum hydride (1M solution in tetrahydrofuran) is slowlyadded dropwise. The reaction mixture is stirred for 4 hours at ambienttemperature. Then 0.55 mL of 1N sodium hydroxide solution and 0.50 mL ofwater are added, the mixture is boiled for 0.3 hours, then cooled again.It is filtered, the filtrate is dried and evaporated to dryness. Theresidue is extracted with ethyl acetate and 1 N hydrochloric acid. Theproduct precipitates out, is suction filtered, then extracted with ethylacetate and 1 N sodium hydroxide solution. The organic phase is washedwith water, dried, and evaporated to dryness. The residue is stirredwith petroleum ether. 0.513 g of product V (84%) is obtained as a solid(m.p. 176-178° C.). ¹H NMR (400 MHz, DMSO): 7.24 (2H, d); 6.98 (2H, d);6.30 (2H, s); 3.77-3.68 (4H, m); 3.22 (2H, t); 3.17-3.09 (4H, m); 2.99(2H, t).

Synthesis ofmono-{4-[4-(4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)piperazin-1-yl]phenyl}sulfate(V According to Scheme 13) (Example 291)

0.100 g (0.269 mmol) of{2-[4-(4-hydroxyphenyl)piperazin-1-yl]-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl}propylamineis dissolved in 3 mL of pyridine at ambient temperature, and 0.009 g(0.0540 mmol) of potassium iodide is added. Then 0.089 mL (1.34 mmol) ofchlorosulfonic acid is added dropwise while cooling with ice. After theaddition, the reaction mixture is solid and 3 mL of tetrahydrofuran isadded. Then it is combined with water and dichloromethane, and theprecipitate formed is suction filtered and dried. 0.049 g of the product(33%) is obtained as a powder. ¹H NMR (400 MHz, DMSO+DCl): 9.01-8.92(1H, m); 8.21-8.10 (1H, m); 7.90-7.80 (1H, m); 7.79-7.70 (1H, m);7.40-7.31 (1H, m); 7.02-6.92 (1H, m); 4.49-4.27 (4H, m); 3.82-3.64 (4H,m); 3.57-3.30 (6H, m); 1.65-1.50 (2H, m); 0.96-0.77 (3H, m).

Synthesis of2-[4-(4-chlorophenyl)piperazin-1-yl]-4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-7-oltriflate (Example 378) (X According to Scheme 14)

thieno[3,2-d]pyrimidine-2,4-diol (II): 10.0 g (64.0 mmol) of methylester3-aminothiophene-2-carboxylate (I) and 19.0 g (31.60 mmol) of urea aremixed and melted for 2 hours at 200° C. After cooling, the reactionmixture is dissolved in 1 molar sodium hydroxide solution anddecolorized with activated charcoal. It is filtered and the filtrate iscooled and acidified with 4M hydrochloric acid. The precipitate formedis suction filtered and dried. 8.03 g of product II (75%) is obtained asa powder.

2,4-dichlorothieno[3,2-d]pyrimidine (III): 7.97 g (47.0 mmol) ofthieno[3,2-d]pyrimidine-2,4-diol (II) is placed in 50 mL (54.5 mmol) ofphosphorus oxychloride, then refluxed for 14 hours, with stirring. Themixture is then concentrated by evaporation, the residue is combinedwith ice water. The precipitate formed is suction filtered and dried.9.00 g of product III (93%) is obtained as a powder.

(2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (IV): 3.95 g (19.26mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (III), 1.90 mL (23.11 mmol)of propylamine, and 6.71 mL (38.52 mmol) of diisopropylethylamine arestirred for 16 hours in 40 mL of tetrahydrofuran at ambient temperature.Then the reaction mixture is concentrated by evaporation, the residue iscombined with water. The precipitate formed is suction filtered anddried. 4.03 g of product IV (92%) is obtained as a powder.

(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (V): 8.34 g(36.63 mmol) of (2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (IV) isdissolved in 60 mL of acetonitrile and 7.89 g (44.32 mmol) ofN-bromosuccinimide is added. The reaction mixture is stirred for 16hours at ambient temperature and for 6 hours at 50° C. Then it isconcentrated by evaporation and the residue is combined with water. Theprecipitate formed is suction filtered, washed, and dried. 7.25 g ofproduct V (61%) is obtained as a powder.

{7-bromo-2-[4-(4-chlorophenyl)piperazin-1-yl]thieno[3,2-d]pyrimidin-4-yl}propylamine(VII): 2.00 g (6.20 mmol) of(7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-yl)propylamine (V), 4.64 g(23.59 mmol) of 1-(4-chlorophenyl)piperazine (VI), and 2.13 mL (12.39mmol) of diisopropylethylamine are placed in 15 mL of dioxane and heatedto 100° C. in the microwave for 0.75 hours. As only 50% reacted, thereaction mixture is heated to 160° C. in the microwave for another 1.5hours. Then the precipitate formed is suction filtered, washed withwater, and stirred with petroleum ether. After suction filtering again,3.19 g of product VII (100%) is obtained.

{2-[4-(4-chlorophenyl)piperazin-1-yl]-7-methoxythieno[3,2-d]pyrimidin-4-yl}propylamine(VIII): 2.00 g (4.28 mmol) of{7-bromo-2-[4-(4-chlorophenyl)piperazin-1-yl]thieno[3,2-d]pyrimidin-4-yl}propylamine(VII) is placed in 15 mL of methanol and cooled to some extent. First0.995 g (18.42 mmol) of sodium methoxide, then 0.187 g (2.36 mmol) ofcopper (II) oxide, and 0.040 g (0.27 mmol) of sodium iodide are added.The reaction mixture is heated to 160° C. in the microwave for 0.75hours. Then it is suction filtered through silica gel and the motherliquor is concentrated by evaporation. The residue is dissolved and anyinsoluble matter is removed by suction filtering. Further purificationis carried out by preparative HPLC. 0.23 g of product VIII (20%) isobtained.

2-[4-(4-chlorophenyl)piperazin-1-yl]-4-propylaminothieno[3,2-d]pyrimidin-7-oltriflate (IX): 0.430 g (1.03 mmol) of{2-[4-(4-chlorophenyl)piperazin-1-yl]-7-methoxythieno[3,2-d]pyrimidin-4-yl}propylamine(VIII) is dissolved in 4 mL of dichloromethane and cooled somewhat.Under a nitrogen atmosphere, 1.13 mL (1.13 mmol) of boron tribromidesolution (1M in heptane) is added dropwise. The reaction mixture isstirred for 48 hours at ambient temperature. After the addition of 0.50mL of boron tribromide solution, the mixture is stirred for another 24hours at ambient temperature. Then saturated potassium carbonatesolution is added and the mixture is stirred for 0.4 hours. After theaddition of dichloromethane, the organic phase is separated off throughthe phase separator and evaporated to dryness. The residue is purifiedby chromatography (HPLC), corresponding fractions are lyophilized. 0.150g of product IX (28%) is obtained.

2-[4-(4-chlorophenyl)piperazin-1-yl]-4-propylamino-6,7-dihydrothieno[3,2-d]pyrimidin-7-oltriflate (X): 0.050 g (0.12 mmol) of2-[4-(4-chlorophenyl)piperazin-1-yl]-4-propylaminothieno[3,2-d]pyrimidin-7-oltriflate (IX) is dissolved in 1 mL of methanol and 0.020 g (0.53 mmol)of sodium borohydride is added. The reaction mixture is stirred for 16hours at ambient temperature, then concentrated by evaporation. Theresidue is purified by chromatography using HPLC through an RP column(column: Microsorb, RP-C18). Corresponding fractions are combined andlyophilized. 0.013 g of product X (20%) is obtained as a powder. ¹H NMR(400 MHz, DMSO): 7.26 (2H, d); 7.00 (2H, d); 5.15-5.09 (1H, m);3.86-3.79 (4H, m), 3.63-3.55 (2H, m); 3.42-3.33 (2H, m); 3.28-3.22 (4H,m); 3.18-3.11 (1H, m); 1.63-1.52 (2H, m); 0.88 (3H, t).

The following Examples may be prepared analogously to the methods ofsynthesis described above illustrated in Schemes 1 to 14 (as indicated).The compounds are suitable as PDE4-inhibitors and have IC₅₀ values ofless than or equal to 1 μmol.

# R¹ R² R³ Preparation 1. H

Scheme 1 2. H

Scheme 1 3. H

Scheme 1 4. H

Scheme 1 5. H

Scheme 1 6. H

Scheme 1 7. H

Scheme 1 8. H

Scheme 1 9. H

Scheme 1 10. H

Scheme 1 11. H

Scheme 1 12. H

Scheme 1 13. H

Scheme 1 14. H

Scheme 1 15. H

Scheme 1 16. H

Scheme 1 17. H

Scheme 1 18. H

Scheme 1 19. H

Scheme 1 20. H

Scheme 1 21. H

Scheme 1 22. H

Scheme 1 23. H

Scheme 1 24. H

Scheme 1 25. H

Scheme 1 26. H

Scheme 1 27. H

Scheme 1 28. H

Scheme 1 29. H

Scheme 1 30. H

Scheme 1 31. H

Scheme 1 32. H

Scheme 1 33. H

Scheme 1 34. H

Scheme 1 35. H

Scheme 1 36. H

Scheme 1 37. H

Scheme 1 38. H

Scheme 1 39. H

Scheme 1 40. H

Scheme 1 41. H

Scheme 1 42. H

Scheme 1 43. H

Scheme 1 44. H

Scheme 1 45. H

Scheme 1 46. H

Scheme 1 47. H

Scheme 1 48. H

Scheme 1 49. H

Scheme 1 50. H

Scheme 1 51. H

Scheme 1 52. H

Scheme 1 53. H

Scheme 1 54. H

Scheme 1 55. H

Scheme 1 56. H

Scheme 1 57. H

Scheme 1 58. H

Scheme 1 59. H

Scheme 1 60. H

Scheme 1 61. H

Scheme 1 62. H

Scheme 1 63. H

Scheme 1 64. H

Scheme 1 65. H

Scheme 1 66. H

Scheme 1 67. H

Scheme 1 68. H

Scheme 1 69. H

Scheme 1 70. H

Scheme 1 71. H

Scheme 1 72. H

Scheme 1 73. H

Scheme 1 74. H

Scheme 1 75. H

Scheme 1 76. H

Scheme 1 77. H

Scheme 1 78. H

Scheme 1 79. H

Scheme 1 80. H

Scheme 1 81. H

Scheme 1 82. H

Scheme 1 83. H

Scheme 1 84. H

Scheme 2 85. H

Scheme 2 86. H

Scheme 2 87. H

Scheme 2 88. H

Scheme 2 89. H

Scheme 2 90. H

Scheme 2 91. H

Scheme 2 92. H

Scheme 2 93. H

Scheme 1 94. H

Scheme 2 95. H

Scheme 2 96. H

Scheme 2 97. H

Scheme 2 98. H

Scheme 5 99. H

Scheme 1 100. H

Scheme 1 101. H

Scheme 5 102. H

Scheme 5 103. H

Scheme 1 104. H

Scheme 1 105. H

Scheme 1 106. H

Scheme 1 107. H

Scheme 7 108. H

Scheme 1 109. H

 Scheme 11 110. H

Scheme 1 111. H

Scheme 1 112. H

Scheme 1 113. H

Scheme 1 114. H

Scheme 1 115. H

Scheme 1 116. H

Scheme 1 117. H

Scheme 1 118. H

Scheme 1 119. H

 Scheme 10 120. H

 Scheme 10 121. H

 Scheme 10 122. H

 Scheme 10 123. H

 Scheme 10 124. H

 Scheme 12 125. H

 Scheme 12 126. H

 Scheme 12 127. H

 Scheme 10 128. H

 Scheme 12 129. H

 Scheme 12 130. H

Scheme 2 131. H

Scheme 2 132. H

Scheme 2 133. H

Scheme 2 134. H

Scheme 2 135. H

Scheme 2 136. H

Scheme 2 137. H

Scheme 2 138. H

Scheme 2 139. H

Scheme 2 140. H

Scheme 2 141. H

Scheme 2 142. H

Scheme 2 143. H

Scheme 2 144. H

Scheme 2 145. H

Scheme 2 146. H

Scheme 2 147. H

Scheme 2 148. H

Scheme 2 149. H

Scheme 2 150. H

Scheme 2 151. H

Scheme 2 152. H

Scheme 2 153. H

Scheme 2 154. H

Scheme 2 155. H

Scheme 2 156. H

Scheme 2 157. H

Scheme 2 158. H

Scheme 2 159. H

Scheme 2 160. H

Scheme 2 161. H

Scheme 2 162. H

Scheme 2 163. H

Scheme 2 164. H

Scheme 2 165. H

Scheme 2 166. H

Scheme 2 167. H

Scheme 2 168. H

Scheme 2 169. H

Scheme 2 170. H

Scheme 2 171. H

Scheme 2 172. H

Scheme 2 173. H

Scheme 2 174. H

Scheme 2 175. H

Scheme 2 176. H

Scheme 2 177. H

Scheme 2 178. H

Scheme 2 179. H

Scheme 2 180. H

Scheme 2 181. H

Scheme 2 182. H

Scheme 2 183. H

Scheme 2 184. H

Scheme 2 185. H

Scheme 2 186. H

Scheme 2 187. H

Scheme 2 188. H

Scheme 2 189. H

Scheme 2 190. H

Scheme 2 191. H

Scheme 2 192. H

Scheme 2 193. H

Scheme 2 194. H

Scheme 2 195. H

Scheme 2 196. H

Scheme 2 197. H

Scheme 2 198. H

Scheme 2 199. H

Scheme 2 200. H

Scheme 2 201. H

Scheme 2 202. H

Scheme 2 203. H

Scheme 2 204. H

Scheme 2 205. H

Scheme 2 206. H

Scheme 2 207. H

Scheme 2 208. H

Scheme 2 209. H

Scheme 1 210. H

Scheme 1 211. H

Scheme 1 212. H

Scheme 1 213. H

Scheme 1 214. H

Scheme 1 215. H

Scheme 4 216. H

Scheme 1 217. H

Scheme 1 218. H H

Scheme 1 219. H H

Scheme 1 220. H

Scheme 1 221. H

Scheme 1 222. H

Scheme 1 223. H

Scheme 1 224. H

Scheme 1 225. H

Scheme 1 226. H

Scheme 5 227. H

Scheme 5 228. H

Scheme 5 229. H

Scheme 5 230. H

 Scheme 10 231. H

Scheme 5 232. H

Scheme 5 233. H

Scheme 5 234. H

Scheme 5 235. H

Scheme 5 236. H

 Scheme 12 237. H

Scheme 4 238. H

Scheme 4 239. H

Scheme 4 240. H

Scheme 4 241. H

Scheme 5 242. H

Scheme 5 243. H

Scheme 5 244. H

Scheme 5 245. H

Scheme 5 246. H

Scheme 5 247. H

Scheme 5 248. H

Scheme 5 249. H

Scheme 5 250. H

Scheme 5 251. H

Scheme 5 252. H

Scheme 5 253. H

Scheme 5 254. H

Scheme 5 255. H

Scheme 5 256. H

Scheme 5 257. H

Scheme 5 258. H

Scheme 5 259. H

Scheme 5 260. H

Scheme 5 261. H

Scheme 5 262. H

Scheme 5 263. H

Scheme 5 264. H

Scheme 5 265. H

Scheme 5 266. H

Scheme 5 267. H

Scheme 5 268. H

Scheme 5 269. H

Scheme 5 270. H

Scheme 5 271. H

Scheme 5 272. H

Scheme 5 273. H

Scheme 5 274. H

Scheme 7 275. H

Scheme 7 276. H

Scheme 7 277. H

Scheme 7 278. H

Scheme 7 279. H

Scheme 7 280. H

Scheme 7 281. H

Scheme 7 282. H

 Scheme 10 283. H

 Scheme 10 284. H

 Scheme 10 285. H

 Scheme 10 286. H

 Scheme 10 287. H

 Scheme 10 288. H

 Scheme 10 289. H

 Scheme 10 290. H

Scheme 1 291. H

Scheme 1 292. H

Scheme 1 293. H

Scheme 1 294. H

Scheme 1 295. H

Scheme 1 296. H

Scheme 1

# R¹ R² R³ Preparation 297. H

Scheme 8 298. H

Scheme 8 299. H

Scheme 8 300. H

Scheme 8 301. H

Scheme 8 302. H

Scheme 8

# NR¹R² R³ Preparation 303.

Scheme 1

Further Examples include: # Structure Preparation 304.

Scheme 1 305.

306.

Scheme 1 307.

Scheme 1 308.

Scheme 1 309.

Scheme 1

Examples A1

# R¹ R² R³ Preparation 310. H

Scheme 7 311. H

Scheme 12 312. H

Scheme 1 313. H

Scheme 1 314. H

Scheme 1 315. H

Scheme 1 316. H

Scheme 1 317. H

Scheme 1 318. H

Scheme 1 319. H

Scheme 12 320. H

Scheme 1 321. H

Scheme 2 322. H

Scheme 1 323. H

Scheme 1 324. H

Scheme 1 325. H

Scheme 1 326. H

Scheme 1 327. H

Scheme 1 328. H

Scheme 1 329. H

Scheme 1 330. H

Scheme 1 331. H

Scheme 1 332. H

Scheme 1 333. H

Scheme 1 334. H

Scheme 1 335. H

Scheme 1 336. H

Scheme 1 337. H

Scheme 1 338. H

Scheme 1 339. H

Scheme 1 340. H

Scheme 1 341. H

Scheme 1 342. H

Scheme 1 343. H

Scheme 1 344. H

Scheme 1 345. H

Scheme 1 346. H

Scheme 1 347. H

Scheme 1 348. H

Scheme 1 349. H

Scheme 1 350. H

Scheme 1 351. H

Scheme 1 352. H

Scheme 1 353. H

Scheme 1 354. H

Scheme 1 355. H

Scheme 1 356. H

Scheme 1 357. H

Scheme 11 358. H

Scheme 11 359. H

Scheme 1 360. H

Scheme 12 361. H

Scheme 11 362. H

Scheme 11 363. H

Scheme 11 364. H

Scheme 11 365. H

Scheme 1 366. H

Scheme 1

Examples B1

# R¹ R² R³ Preparation 367. H

Scheme 1 368. H

Scheme 1 Enantiomer 2 of racemate 297 369. H

Scheme 1 370. H

Scheme 1 Enantiomer 1 of racemate 300 371. H

Scheme 1 Enantiomer 2 of racemate 300 372. H

Scheme 1

Examples C1

# NR¹R² R³ Preparation 373.

Scheme 1 374.

Scheme 1

Further Examples include: Examples D1 # Structure Preparation 375.

Scheme 9 376.

Scheme 9 377.

Scheme 9 378.

Scheme 14

Indications

As has been found, the compounds of formula 1 are characterized by theirwide range of applications in the therapeutic field. Particular mentionshould be made of those applications for which the compounds accordingto the invention of formula 1 are preferably suited on account of theirpharmaceutical efficacy as PDE4 inhibitors. Examples include respiratoryor gastrointestinal diseases or complaints, inflammatory diseases of thejoints, skin, or eyes, cancers, and also diseases of the peripheral orcentral nervous system.

Particular mention should be made of the prevention and treatment ofdiseases of the airways and of the lung which are accompanied byincreased mucus production, inflammations, and/or obstructive diseasesof the airways. Examples include acute, allergic, or chronic bronchitis,chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema,allergic or non-allergic rhinitis or sinusitis, chronic rhinitis orsinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways,infectious bronchitis or pneumonitis, pediatric asthma, bronchiectases,pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome),bronchial edema, pulmonary edema, bronchitis, pneumonia or interstitialpneumonia triggered by various causes, such as aspiration, inhalation oftoxic gases, or bronchitis, pneumonia or interstitial pneumonia as aresult of heart failure, irradiation, chemotherapy, cystic fibrosis, ormucoviscidosis, or alpha1-antitrypsin deficiency.

Also deserving special mention is the treatment of inflammatory diseasesof the gastrointestinal tract. Examples include acute or chronicinflammatory changes in gall bladder inflammation, Crohn's disease,ulcerative colitis, inflammatory pseudopolyps, juvenile polyps, colitiscystica profunda, pneumatosis cystoides intestinales, diseases of thebile duct, and gall bladder, e.g., gallstones and conglomerates, for thetreatment of inflammatory diseases of the joints such as rheumatoidarthritis or inflammatory diseases of the skin and eyes.

Preferential mention should also be made of the treatment of cancers.Examples include all forms of acute and chronic leukemias such as acutelymphatic and acute myeloid leukemia, chronic lymphatic and chronicmyeloid leukemia, and bone tumors such as osteosarcoma and all types ofglioma such as oligodendroglioma and glioblastoma.

Preferential mention should also be made of the prevention and treatmentof diseases of the peripheral or central nervous system. Examples ofthese include depression, bipolar or manic depression, acute and chronicanxiety states, schizophrenia, Alzheimer's disease, Parkinson's disease,acute and chronic multiple sclerosis, or acute and chronic pain as wellas injuries to the brain caused by stroke, hypoxia, or craniocerebraltrauma.

Particularly preferably the present invention relates to the use ofcompounds of formula 1 for preparing a pharmaceutical composition forthe treatment of inflammatory or obstructive diseases of the upper andlower respiratory tract including the lungs, such as, for example,allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis,idiopathic pulmonary fibrosis, fibrosing alveolitis, COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, particularly COPD, chronic bronchitis, and asthma.

It is most preferable to use the compounds of formula 1 for thetreatment of inflammatory and obstructive diseases such as COPD, chronicbronchitis, chronic sinusitis, asthma, Crohn's disease, ulcerativecolitis, particularly COPD, chronic bronchitis, and asthma.

It is also preferable to use the compounds of formula 1 for thetreatment of diseases of the peripheral or central nervous system suchas depression, bipolar or manic depression, acute and chronic anxietystates, schizophrenia, Alzheimer's disease, Parkinson's disease, acuteand chronic multiple sclerosis, or acute and chronic pain as well asinjuries to the brain caused by stroke, hypoxia, or craniocerebraltrauma.

An outstanding aspect of the present invention is the reduced profile ofside effects. This means, within the scope of the invention, being ableto administer a dose of a pharmaceutical composition without inducingvomiting, preferably nausea and most preferably malaise in the patient.It is particularly preferable to be able to administer a therapeuticallyeffective quantity of substance without inducing emesis or nausea, atevery stage of the disease.

Combinations

The compounds of formula 1 may be used on their own or in conjunctionwith other active substances of formula 1 according to the invention. Ifdesired the compounds of formula 1 may also be used in combination withother pharmacologically active substances. It is preferable to use forthis purpose active substances selected, for example, from amongbetamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors,LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines,PAF-antagonists, and PI3-kinase inhibitors or double or triplecombinations thereof, such as, for example, combinations of

-   -   betamimetics with corticosteroids, PDE4-inhibitors,        EGFR-inhibitors, or LTD4-antagonists,    -   anticholinergics with betamimetics, corticosteroids,        PDE4-inhibitors, EGFR-inhibitors, or LTD4-antagonists,    -   corticosteroids with PDE4-inhibitors, EGFR-inhibitors, or        LTD4-antagonists    -   PDE4-inhibitors with EGFR-inhibitors, or LTD4-antagonists    -   EGFR-inhibitors with LTD4-antagonists    -   MRP4-inhibitors.

The invention also encompasses combinations of three active substances,each selected from one of the abovementioned categories of compounds.

Suitable betamimetics used are preferably compounds selected from amongalbuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol,fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol,isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine,metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol,rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulfonterol,tiaramide, terbutaline, tolubuterol, is CHF-1035, HOKU-81, KUL-1248,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexyloxy}butyl)benzylsulfonamide,5-[2-(5.6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxyacetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyaceticacid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-2-methylpropyl}phenoxy)butyricacid,8-{2-[2-(3.4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,and1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomers, andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates, or hydrates thereof.

Preferably the betamimetics are selected from among bambuterol,bitolterol, carbuterol, clenbuterol, fenoterol, formoterol,hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol,sulfonterol, terbutaline, tolubuterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexyloxy}butyl)benzenesulfonamide,5-[2-(5.6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one,4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulfonyl}ethyl]amino}ethyl]-2(3H)benzothiazolone,1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl-4-phenoxyacetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyaceticacid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-2-methylpropyl}phenoxy)butyricacid,8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,and1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol,optionally in the form of the racemates, enantiomers, diastereomers, andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates, or hydrates thereof.

Particularly preferred betamimetics are selected from among fenoterol,formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexyloxy}butyl)benzenesulfonamide,5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-one,1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol,1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxyacetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyaceticacid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-2-methylpropyl}phenoxy)butyricacid,8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,and1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,optionally in the form of the racemates, enantiomers, diastereomers, andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates, or hydrates thereof.

Of these betamimetics the particularly preferred ones according to theinvention are formoterol, salmeterol,3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylphenyl)ethylamino]hexyloxy}butyl)benzenesulfonamide,6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(ethyl4-phenoxyacetate)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyaceticacid)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)ethylamino]-2-methylpropyl}phenoxy)butyricacid,8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,and5-[2-(5,6-diethylindan-2-ylamino)-1-hydroxyethyl]-8-hydroxy-1H-quinoline-2-one,optionally in the form of the racemates, enantiomers, diastereomers, andoptionally in the form of the pharmacologically acceptable acid additionsalts, solvates, or hydrates thereof.

According to the invention the acid addition salts of the betamimeticsare preferably selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate,hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, andhydro-p-toluenesulfonate, preferably the hydrochloride, hydrobromide,hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate.Of the abovementioned acid addition salts the salts of hydrochloricacid, methanesulfonic acid, benzoic acid, and acetic acid areparticularly preferred according to the invention.

The anticholinergics used are preferably compounds selected from amongthe tiotropium salts, oxitropium salts, flutropium salts, ipratropiumsalts, glycopyrronium salts, trospium salts, tropenol2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionatemethobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide,tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol3,3′,4,4′-tetrafluorobenzilate methobromide, scopine3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilatemethobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine3,3′-difluorobenzilate methobromide, tropenol9-hydroxyfluorene-9-carboxylate methobromide, tropenol9-fluorofluorene-9-carboxylate methobromide, scopine9-hydroxyfluoren-9-carboxylate methobromide, scopine9-fluorofluorene-9-carboxylate methobromide, tropenol9-methylfluorene-9-carboxylate methobromide, scopine9-methylfluorene-9-carboxylate methobromide, cyclopropyltropinebenzilate methobromide, cyclopropyltropine 2,2-diphenylpropionatemethobromide, cyclopropyltropine 9-hydroxyxanthene-9-carboxylatemethobromide, cyclopropyltropine 9-methylfluorene-9-carboxylatemethobromide, cyclopropyltropine 9-methylxanthene-9-carboxylatemethobromide, cyclopropyltropine 9-hydroxyfluorene-9-carboxylatemethobromide, methyl-cyclopropyltropine 4,4′-difluorobenzilatemethobromide, tropenol 9-hydroxyxanthene-9-carboxylate methobromide,scopine 9-hydroxyxanthene-9-carboxylate methobromide, tropenol9-methylxanthene-9-carboxylate methobromide, scopine9-methylxanthene-9-carboxylate methobromide, tropenol9-ethylxanthene-9-carboxylate methobromide, tropenol9-difluoromethylxanthene-9-carboxylate methobromide, scopine9-hydroxymethylxanthene-9-carboxylate methobromide, optionally in theform of the solvates, or hydrates thereof.

In the abovementioned salts the cations tiotropium, oxitropium,flutropium, ipratropium, glycopyrronium, and trospium are thepharmacologically active ingredients. As anions, the abovementionedsalts may preferably contain chloride, bromide, iodide, sulfate,phosphate, methanesulfonate, nitrate, maleate, acetate, citrate,fumarate, tartrate, oxalate, succinate, benzoate, or p-toluenesulfonate,while chloride, bromide, iodide, sulfate, methanesulfonate, orp-toluenesulfonate are preferred as counter-ions. Of all the salts, thechlorides, bromides, iodides, and methanesulfonate are particularlypreferred.

Of particular importance is tiotropium bromide. In the case oftiotropium bromide the pharmaceutical combinations according to theinvention preferably contain it in the form of the crystallinetiotropium bromide monohydrate, which is known from WO 02/30928. If thetiotropium bromide is used in anhydrous form in the pharmaceuticalcombinations according to the invention, it is preferable to useanhydrous crystalline tiotropium bromide, which is known from WO03/000265.

Corticosteroids used here are preferably compounds selected from amongprednisolone, prednisone, butixocortpropionate, flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort,RPR-106541, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothionate,and (S)-(2-oxotetrahydrofuran-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers, or diastereomersthereof, and optionally in the form of the salts and derivatives,solvates, and/or hydrates thereof.

Particularly preferred is the steroid selected from among flunisolide,beclomethasone, triamcinolone, budesonide, fluticasone, mometasone,ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-1,7-carbothionate,and (S)-(2-oxotetrahydrofuran-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxyandrosta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers, or diastereomersthereof, and optionally in the form of the salts and derivatives,solvates, and/or hydrates thereof.

Particularly preferred is the steroid selected from among budesonide,fluticasone, mometasone, ciclesonide, and (S)-fluoromethyl6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothionate,optionally in the form of the racemates, enantiomers, or diastereomersthereof, and optionally in the form of the salts and derivatives,solvates, and/or hydrates thereof.

Any reference to steroids includes a reference to any salts orderivatives, hydrates, or solvates thereof which may exist. Examples ofpossible salts and derivatives of the steroids may be: alkali metalsalts, such as, for example, sodium or potassium salts, sulfobenzoates,phosphates, isonicotinates, acetates, propionates, dihydrogenphosphates, palmitates, pivalates, or furoates thereof.

Other PDE4 inhibitors which may be used are preferably compoundsselected from among enprofyllin, theophyllin, roflumilast, ariflo(cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram,D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418,PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888,YM-58997,Z-15370,N-(3,5-dichloro-1-oxopyridin-4-yl)-4-difluoromethoxy-3-yclopropylmethoxybenzamide,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone,3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methylisothioureido]benzyl)-2-pyrrolidone,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,(S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,and9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers, or diastereomers,and optionally in the form of the pharmacologically acceptable acidaddition salts, solvates, and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from amongenprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram,AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, Cl-1018,CDC-801, D-22888, YM-58997, Z-15370,N-(3,5-dichloro-1-oxopyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide,cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid],2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,and9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers, or diastereomers,and optionally in the form of the pharmacologically acceptable acidaddition salts, solvates, and/or hydrates thereof.

Particularly preferably the PDE4-inhibitor is selected from amongroflumilast, ariflo (cilomilast), arofyllin, AWD-12-281 (GW-842470),2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one,cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol],atizoram, Z-15370,9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,and9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine,optionally in the form of the racemates, enantiomers, or diastereomers,and optionally in the form of the pharmacologically acceptable acidaddition salts, solvates, and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theabovementioned PDE4-inhibitors might be in a position to form are meant,for example, salts selected from among the hydrochloride, hydrobromide,hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate,hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate,hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate,hydrobenzoate, and hydro-p-toluenesulfonate, preferably hydrochloride,hydrobromide, hydrosulfate, hydrophosphate, hydrofumarate, andhydromethanesulfonate.

LTD4-antagonists which may be used are preferably compounds selectedfrom among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523),MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321,1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane acetic acid,1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic acid, and[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]aceticacid, optionally in the form of the racemates, enantiomers, ordiastereomers, optionally in the form of the pharmacologicallyacceptable acid addition salts, and optionally in the form of the saltsand derivatives, solvates, and/or hydrates thereof.

Preferably the LTD4-antagonist is selected from among montelukast,pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507),VUF-5078, VUF-K-8707, and L-733321, optionally in the form of theracemates, enantiomers, or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts, and optionally in theform of the salts and derivatives, solvates, and/or hydrates thereof.

Particularly preferably the LTD4-antagonist is selected from amongmontelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, andMEN-91507 (LM-1507), optionally in the form of the racemates,enantiomers, or diastereomers, optionally in the form of thepharmacologically acceptable acid addition salts, and optionally in theform of the salts and derivatives, solvates, and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theLTD4-antagonists may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, andhydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide,hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate.By salts or derivatives which the LTD4-antagonists may be capable offorming are meant, for example: alkali metal salts, such as, forexample, sodium or potassium salts, alkaline earth metal salts,sulfobenzoates, phosphates, isonicotinates, acetates, propionates,dihydrogen phosphates, palmitates, pivalates, or furoates.

The EGFR-inhibitors used are preferably compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethokyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis-(2-methoxyethyl)amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6,7-bis-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propyloxy]-6-[(vinylcarbonyl)amino]quinazoline,4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxyquinoline,4-{[3-chloro-4-(3-fluorobenzyloxy)phenyl]amino}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[4-(2-oxomorpholin-4-yl)piperidin-1-yl]ethoxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(tert-butyloxycarbonyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methoxymethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(piperidin-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-acetylaminoethyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylaminoethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylaminoethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-aminocarbonylmethylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxy-quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-ethansulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-ethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-methoxyacetyl)piperidin-4-yloxy]-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-[1-(tert-butyloxycarbonyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(4-methylpiperazin-1-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-(2-methoxyethoxy)quinazoline,4-[(3-ethynylphenyl)amino]-6-(1-acetylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-isopropyloxycarbonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[N-(2-methoxyacetyl)-N-methylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-[1-(2-methoxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(cis-2,6-dimethylmorpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methylmorpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(S,S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethylamino)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-ethylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(3-methoxypropylamino)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline,cetuximab, trastuzumab, ABX-EGF, and Mab ICR-62, optionally in the formof the racemates, enantiomers, or diastereomers thereof, optionally inthe form of the pharmacologically acceptable acid addition saltsthereof, the solvates, and/or hydrates thereof.

Preferred EGFR-inhibitors are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-(N,N-bis-(2-methoxyethyl)amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-ethylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6,7-bis-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)propyloxy]-6-[(vinyl-carbonyl)amino]quinazoline,4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxyquinoline,4-{[3-chloro-4-(3-fluorobenzyloxy)phenyl]amino}-6-(5-{[(2-methanesulfonylethyl)amino]methyl}furan-2-yl)quinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxyethyl)amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-7-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[4-(2-oxomorpholin-4-yl)piperidin-1-yl]ethoxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(tert-butyloxycarbonyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(methoxymethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(piperidin-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-acetylaminoethyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylaminoethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulfonylaminoethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-aminocarbonylmethylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-ethansulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-ethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-methoxyacetyl)piperidin-4-yloxy]-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-acetylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-[1-(tert-butyloxycarbonyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(4-methylpiperazin-1-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-(2-methoxyethoxy)quinazoline,4-[(3-ethynylphenyl)amino]-6-(1-acetylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-isopropyloxycarbonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[N-(2-methoxyacetyl)-N-methylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(piperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-[1-(2-methoxyacetyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(cis-2,6-dimethylmorpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methylmorpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(S,S)-(2-oxa-5-azabicyclo[2,2,1]hept-5-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethylamino)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-ethylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(3-methoxypropylamino)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxylquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline,and cetuximab, optionally in the form of the racemates, enantiomers, ordiastereomers thereof, optionally in the form of the pharmacologicallyacceptable acid addition salts thereof, the solvates, and/or hydratesthereof.

It is particularly preferable within the scope of the present inventionto use those EGFR-inhibitors which are selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(R)-(1-phenylethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6,7-bis-(2-methoxyethoxy)quinazoline,4-[(R)-(1-phenylethyl)amino]-6-(4-hydroxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine,3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxyquinoline,4-[(R)-(1-phenylethyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{2-[4-(2-oxomorpholin-4-yl)piperidin-1-yl]ethoxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-aminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(piperidin-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-acetylaminoethyl)piperidin-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-ethansulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[1-(2-methoxyacetyl)piperidin-4-yloxy]-7-(2-methoxyethoxy)quinazoline,4-[(3-ethynylphenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]cyclohexan-1-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-acetylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7(2-methoxyethoxy)quinazoline,4-[(3-ethynylphenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethylamino)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-ethylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino-6-[trans-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline,and4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,optionally in the form of the racemates, enantiomers, or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts thereof, the solvates, and/or hydrates thereof.

Particularly preferred EGFR-inhibitors according to the invention arethe compounds selected from among4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-((R)-6-methyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-((S)-6-methyl-2-oxomorpholin-4-yl)ethoxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxyethyl)-N-methylamino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxyquinazoline,4-[(3-ethynylphenyl)amino]-6,7-bis-(2-methoxyethoxy)quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]quinazoline,4-[(3-ethynylphenyl)amino]-6-{[4-(5,5-dimethyl-2-oxomorpholin-4-yl)-1-oxo-2-buten-1-yl]amino}quinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methanesulfonylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-acetylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,4-[(3-ethynylphenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]piperidin-4-yloxy}-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[cis-4-(N-acetyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-methylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[trans-4-(N-methanesulfonyl-N-methylamino)cyclohexan-1-yloxy]-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-dimethylaminocyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methylamino}cyclohexan-1-yloxy)-7-methoxyquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-[2-(2,2-dimethyl-6-oxomorpholin-4-yl)ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxylquinazoline,4-[(3-chloro-4-fluorophenyl)amino]-6-(1-methanesulfonylpiperidin-4-yloxy)-7-methoxyquinazoline,and4-[(3-chloro-4-fluorophenyl)amino]-6-(1-cyanopiperidin-4-yloxy)-7-methoxyquinazoline,optionally in the form of the racemates, enantiomers, or diastereomersthereof, optionally in the form of the pharmacologically acceptable acidaddition salts thereof, the solvates, and/or hydrates thereof.

By acid addition salts with pharmacologically acceptable acids which theEGFR-inhibitors may be capable of forming are meant, for example, saltsselected from among the hydrochloride, hydrobromide, hydroiodide,hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate,hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate,hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, andhydro-p-toluenesulfonate, preferably hydrochloride, hydrobromide,hydrosulfate, hydrophosphate, hydrofumarate, and hydromethanesulfonate.

Examples of dopamine agonists which may be used preferably includecompounds selected from among bromocriptine, cabergoline,alpha-dihydroergocryptine, lisuride, pergolide, pramipexole, roxindole,ropinirole, talipexole, terguride, and viozan. Any reference to theabovementioned dopamine agonists within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts and optionally hydrates thereof which may exist. By thephysiologically acceptable acid addition salts which may be formed bythe abovementioned dopamine agonists are meant, for example,pharmaceutically acceptable salts which are selected from the salts ofhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lacticacid, citric acid, tartaric acid, and maleic acid.

Examples of H1-antihistamines preferably include compounds selected fromamong epinastine, cetirizine, azelastine, fexofenadine, levocabastine,loratadine, mizolastine, ketotifen, emedastine, dimethindene,clemastine, bamipine, dexchlorpheniramine, pheniramine, doxylamine,chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine,ebastine, desloratidine, and meclizine. Any reference to theabovementioned H1-antihistamines within the scope of the presentinvention includes a reference to any pharmacologically acceptable acidaddition salts which may exist. Examples of PAF-antagonists preferablyinclude compounds selected from 4-(2-chlorophenyl)-9-methyl-2-[3(4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines,and6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclopenta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.

MRP4-inhibitors used are preferably compounds selected from amongN-acetyldinitrophenylcysteine, cGMP, cholate, diclofenac,dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulfate,dilazep, dinitrophenyl-S-glutathione, estradiol 17-β-glucuronide,estradiol 3,17-disulfate, estradiol 3-glucuronide, estradiol 3-sulfate,estrone 3-sulfate, flurbiprofen, folate, N⁵-formyltetrahydrofolate,glycocholate, clycolithocholic acid sulfate, ibuprofen, indomethacin,indoprofen, ketoprofen, lithocholic acid sulfate, methotrexate, MK571((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]propanoicacid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside,probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate,taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholicacid sulfate, topotecan, trequinsin, and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers, andthe pharmacologically acceptable acid addition salts and hydratesthereof.

Preferably the invention relates to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for the treatment of respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitors, theMRP4-inhibitors preferably being selected from amongN-acetyldinitrophenylcysteine, dehydroepiandrosterone 3-sulfate,dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulfate,flurbiprofen, glycocholate, glycolithocholic acid sulfate, ibuprofen,indomethacin, indoprofen, lithocholic acid sulfate, MK571, PSC833,sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate,taurolithocholic acid sulfate, trequinsin, and zaprinast, dipyridamole,optionally in the form of the racemates, enantiomers, diastereomers, andthe pharmacologically acceptable acid addition salts and hydratesthereof.

The invention relates more preferably to the use of MRP4-inhibitors forpreparing a pharmaceutical composition for treating respiratorycomplaints, containing the PDE4B-inhibitors and MRP4-inhibitorsaccording to the invention, the MRP4-inhibitors preferably beingselected from among dehydroepiandrosterone 3-sulfate, estradiol3,17-disulfate, flurbiprofen, indomethacin, indoprofen, MK571,taurocholate, optionally in the form of the racemates, enantiomers,diastereomers, and the pharmacologically acceptable acid addition saltsand hydrates thereof. The separation of enantiomers from the racematescan be carried out using methods known from the art (e.g.,chromatography on chiral phases, etc.).

By acid addition salts with pharmacologically acceptable acids aremeant, for example, salts selected from among the hydrochlorides,hydrobromides, hydroiodides, hydrosulfates, hydrophosphates,hydromethanesulfonates, hydronitrates, hydromaleates, hydroacetates,hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates,hydrooxalates, hydrosuccinates, hydrobenzoates, andhydro-p-toluenesulfonates, preferably the hydrochlorides, hydrobromides,hydrosulfates, hydrophosphates, hydrofumarates, andhydromethanesulfonates.

The invention further relates to pharmaceutical preparations whichcontain a triple combination of the PDE4B-inhibitors, MRP4-inhibitors,and another active substance according to the invention, such as, forexample, an anticholinergic, a steroid, an LTD4-antagonist, or abetamimetic, and the preparation thereof, and the use thereof fortreating respiratory complaints.

Formulations

Suitable forms for administration are, for example, tablets, capsules,solutions, syrups, emulsions, or inhalable powders or aerosols. Thecontent of the pharmaceutically effective compound(s) in each caseshould be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. %of the total composition, i.e., in amounts which are sufficient toachieve the dosage range specified hereinafter.

The preparations may be administered orally in the form of a tablet, asa powder, as a powder in a capsule (e.g., a hard gelatine capsule), as asolution or suspension. When administered by inhalation the activesubstance combination may be given as a powder, as an aqueous oraqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterized bythe content of one or more compounds of formula 1 according to thepreferred embodiments above.

It is particularly preferable if the compounds of formula 1 areadministered orally, and it is also particularly preferable if they areadministered once or twice a day. Suitable tablets may be obtained, forexample, by mixing the active substance(s) with known excipients, forexample, inert diluents such as calcium carbonate, calcium phosphate, orlactose, disintegrants such as corn starch or alginic acid, binders suchas starch or gelatine, lubricants such as magnesium stearate or talc,and/or agents for delaying release, such as carboxymethyl cellulose,cellulose acetate phthalate, or polyvinyl acetate. The tablets may alsocomprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example, collidone or shellac, gum arabic, talc, titaniumdioxide, or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups containing the active substances or combinations thereofaccording to the invention may additionally contain a sweetener such assaccharine, cyclamate, glycerol, or sugar, and a flavor enhancer, e.g.,a flavoring such as vanillin or orange extract. They may also containsuspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Capsules containing one or more active substances or combinations ofactive substances may, for example, be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made, for example, by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

Excipients which may be used include, for example, water,pharmaceutically acceptable organic solvents such as paraffins (e.g.,petroleum fractions), vegetable oils (e.g., groundnut or sesame oil),mono- or polyfunctional alcohols (e.g., ethanol or glycerol), carrierssuch as, e.g., natural mineral powders (e.g., kaolins, clays, talc,chalk), synthetic mineral powders (e.g., highly dispersed silicic acidand silicates), sugars (e.g., cane sugar, lactose, and glucose),emulsifiers (e.g., lignin, spent sulfite liquors, methylcellulose,starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesiumstearate, talc, stearic acid, and sodium lauryl sulfate).

For oral administration the tablets may, of course, contain, apart fromthe abovementioned carriers, additives such as sodium citrate, calciumcarbonate, and dicalcium phosphate together with various additives suchas starch, preferably potato starch, gelatine, and the like. Moreover,lubricants such as magnesium stearate, sodium lauryl sulfate, and talcmay be used at the same time for the tabletting process. In the case ofaqueous suspensions the active substances may be combined with variousflavor enhancers or colorings in addition to the excipients mentionedabove.

It is also preferred if the compounds of formula 1 are administered byinhalation, particularly preferably if they are administered once ortwice a day. For this purpose, the compounds of formula 1 have to bemade available in forms- suitable for inhalation. Inhalable preparationsinclude inhalable powders, propellant-containing metered-dose aerosolsor propellant-free inhalable solutions, which are optionally present inadmixture with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-freeinhalable solutions also includes concentrates or sterile ready-to-useinhalable solutions. The preparations which may be used according to theinvention are described in more detail in the next part of thespecification.

Inhalable Powders

If the active substances of formula 1 are present in admixture withphysiologically acceptable excipients, the following physiologicallyacceptable excipients may be used to prepare the inhalable powdersaccording to the invention: monosaccharides (e.g., glucose orarabinose), disaccharides (e.g., lactose, saccharose, maltose), oligo-and polysaccharides (e.g., dextran), polyalcohols (e.g., sorbitol,mannitol, xylitol), salts (e.g., sodium chloride, calcium carbonate) ormixtures of these excipients with one another. Preferably, mono- ordisaccharides are used, while the use of lactose or glucose ispreferred, particularly, but not exclusively, in the form of theirhydrates. For the purposes of the invention, lactose is the particularlypreferred excipient, while lactose monohydrate is most particularlypreferred. Methods of preparing the inhalable powders according to theinvention by grinding and micronizing and by finally mixing thecomponents together are known from the prior art.

Propellant-Containing Inhalable Aerosols

The propellant-containing inhalable aerosols which may be used accordingto the invention may contain 1 dissolved in the propellant gas or indispersed form. The propellant gases which may be used to prepare theinhalation aerosols according to the invention are known from the priorart. Suitable propellant gases are selected from among hydrocarbons suchas n-propane, n-butane, or isobutane, and halohydrocarbons such aspreferably fluorinated derivatives of methane, ethane, propane, butane,cyclopropane, or cyclobutane. The propellant gases mentioned above maybe used on their own or in mixtures thereof. Particularly preferredpropellant gases are fluorinated alkane derivatives selected from TG134a(1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane),and mixtures thereof. The propellant-driven inhalation aerosols usedwithin the scope of the use according to the invention may also containother ingredients such as co-solvents, stabilizers, surfactants,antioxidants, lubricants, and pH adjusters. All these ingredients areknown in the art.

Propellant-Free Inhalable Solutions

The compounds of formula 1 according to the invention are preferablyused to prepare propellant-free inhalable solutions and inhalablesuspensions. Solvents used for this purpose include aqueous oralcoholic, preferably ethanolic solutions. The solvent may be water onits own or a mixture of water and ethanol. The solutions or suspensionsare adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids.The pH may be adjusted using acids selected from inorganic or organicacids. Examples of particularly suitable inorganic acids includehydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and/orphosphoric acid. Examples of particularly suitable organic acids includeascorbic acid, citric acid, malic acid, tartaric acid, maleic acid,succinic acid, fumaric acid, acetic acid, formic acid, and/or propionicacid, etc. Preferred inorganic acids are hydrochloric and sulfuricacids. It is also possible to use the acids which have already formed anacid addition salt with one of the active substances. Of the organicacids, ascorbic acid, fumaric acid, and citric acid are preferred. Ifdesired, mixtures of the above acids may also be used, particularly inthe case of acids which have other properties in addition to theiracidifying qualities, e.g., as flavorings, antioxidants, or complexingagents, such as citric acid or ascorbic acid, for example. According tothe invention, it is particularly preferred to use hydrochloric acid toadjust the pH.

Co-solvents and/or other excipients may be added to the propellant-freeinhalable solutions used for the purpose according to the invention.Preferred co-solvents are those which contain hydroxyl groups or otherpolar groups, e.g., alcohols—particularly isopropyl alcohol,glycols—particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycol ether, glycerol, polyoxyethylene alcohols, andpolyoxyethylene fatty acid esters. The terms excipients and additives inthis context denote any pharmacologically acceptable substance which isnot an active substance but which can be formulated with the activesubstance or substances in the pharmacologically suitable solvent inorder to improve the qualitative properties of the active substanceformulation. Preferably, these substances have no pharmacological effector, in connection with the desired therapy, no appreciable or at leastno undesirable pharmacological effect. The excipients and additivesinclude, for example, surfactants such as soya lecithin, oleic acid,sorbitan esters, such as polysorbates, polyvinylpyrrolidone, otherstabilizers, complexing agents, antioxidants, and/or preservatives whichguarantee or prolong the shelf life of the finished pharmaceuticalformulation, flavorings, vitamins, and/or other additives known in theart. The additives also include pharmacologically acceptable salts suchas sodium chloride as isotonic agents. The preferred excipients includeantioxidants such as ascorbic acid, for example, provided that it hasnot already been used to adjust the pH, vitamin A, vitamin E,tocopherols, and similar vitamins or provitamins occurring in the humanbody. Preservatives may be used to protect the formulation fromcontamination with pathogens. Suitable preservatives are those which areknown in the art, particularly cetyl pyridinium chloride, benzalkoniumchloride, or benzoic acid or benzoates such as sodium benzoate in theconcentration known from the prior art.

For the treatment forms described above, ready-to-use packs of amedicament for the treatment of respiratory complaints are provided,containing an enclosed description including, for example, the wordsrespiratory disease, COPD, or asthma, a pteridine and one or morecombination partners selected from those described above.

1. A compound of formula 1

wherein: X is O, S, SO, or SO₂; R¹ is H, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene, orC₅-10-heteroaryl-C₁₋₆-alkylene, R² is H or an optionally mono- orpolysubstituted group selected from C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, an optionally mono- or poly-bridged mono- or bicyclicC₃₋₁₀-cycloalkyl, C₆₋₁₀-aryl, an aromatic or non-aromatic, heterocyclicC₃₋₁₀ ring, a bicyclic ring, and a C₆₋₁₀-aryl fused to a C₃₋₁₀heterocycle, or NR¹R² together is a heterocyclic ring optionallysubstituted by one or more groups selected from C₁₋₄-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, straight-chain or branched C₁₋₆-alkanol, andoxo; R³ is a mono- or polysubstituted group selected from a heterocyclicC₆₋₁₀ ring, C₃₋₇-cycloalkyl, C₆₋₁₀-aryl-C₁₋₆-alkylene,C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, a fused, bicyclic ring optionallycontaining 1 to 4 heteroatoms independently selected from N, O, and S,or R³ is optionally substituted phenyl, or R³ is COR^(3.7),COCH₂R^(3.8), CONHR^(3.8), or SO₂R^(3.8), wherein: R^(3.7) is H,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, or C₆₋₁₀-aryl; R^(3.8) isC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₇-cycloalkyl, or a groupselected from C₆₋₁₀-aryl, a heterocyclic C₃₁₀ ring, and a bicyclic ringoptionally substituted by one or more groups selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, halogen, NR^(3.8.1)R^(3.8.2), C₆₋₁₀-aryl,and a heterocyclic C₃₋₁₀ ring, wherein: R^(3.8.1) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, and R^(3.8.2) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl; R⁴ is H, C₁₋₄-alkyl, C₂₋₄-alkenyl,C₂₋₄-alkynyl, or oxo; R⁵ is H, C₁₋₄-alkyl, C₂₋₄-alkenyl, orC₂₋₄-alkynyl; R⁶ is H, C₁₋₄-alkyl, C₂₋₄-alkenyl, or C₂₋₄-alkynyl; R⁷ isH, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₆₋₁₀-aryl, or OH; and R⁸ isH, C₁₋₄-alkyl, C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₆₋₁₀-aryl, or OH; or R⁷ andR⁸ together form oxo; or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 2. The compound of formula 1according to claim 1, wherein: X is O, S, SO, or SO₂; R¹ is H,C₁₋₆-alkyl, C₆₋₁₀-aryl, C₆₋₁₀-aryl-C₁₋₆-alkylene, orC₅₋₁₀-heteroaryl-C₁₋₆-alkylene, R² is H or C₁₋₆-alkyl optionallysubstituted by one or more groups selected from C₁₋₆-haloalkyl, CN,OR^(2.1), NR^(2.1)R^(2.2), COOR^(2.1), CONR^(2.1)R^(2.2),C₃₋₇-cycloalkyl optionally substituted by C₁₋₄-alkyl or oxo, an aromaticor non-aromatic heterocycle optionally substituted by C₁₋₄-alkyl, oxo,OH, or halogen, C₆₋₁₀-aryl optionally substituted by C₁₋₄-alkyl or oxo,and C₆₋₁₀-aryl fused to a C₅₋₆ heterocycle, wherein this fused ringsystem is optionally substituted by C₁₋₄-alkyl or oxo, wherein: R^(2.1)is H or C₁₋₆-alkyl optionally substituted by a C₃₋₇-cycloalkyl, C₃₋₁₀heterocycle, or C₆₋₁₀-aryl, each optionally substituted and R^(2.2) is Hor C₁₋₆-alkyl; or R² is an optionally mono- or poly-bridgedC₃₋₁₀-cycloalkyl or a C₃₋₁₀-cycloalkyl, each optionally fused to aC₆₋₁₀-aryl ring optionally substituted by one or more groups selectedfrom C₁₋₆-alkyl, OH, CH₂OR^(2.3), COOR^(2.3), COR^(2.3),CONR^(2.3)R^(2.4), O—C₁₋₆-alkyl, O—C₇₋₁₁-aralkyl, NR^(2.3)R^(2.4), andNHCOR^(2.5), wherein: R^(2.3) is H or a heterocycle or a C₁₋₆-alkyl,optionally substituted by a group selected from C₃₋₇-cycloalkyl, C₃₋₁₀heterocycle, and C₆₋₁₀-aryl, wherein this group is optionallysubstituted by one or more groups selected from C₁₋₆-alkyl, halogen, OH,and O—C₁₋₆-alkyl, R^(2.4) is H or C₁₋₆-alkyl; R^(2.5) is selected fromthe group consisting of C₃₋₇-cycloalkyl, a heterocyclic C₃₋₁₀ ring, andC₁₋₆-alkyl optionally substituted by OH; or R² is a group of formula 1a

Y is C₁₋₆-alkylene optionally substituted by one or two R^(2.7), whereinR^(2.7) are independently C₁₋₆-alkyl, COOH, CONH₂, OR^(2.1), orCOOR^(2.1), or R^(2.7) together with one or two carbon atoms of Y formsa carbocyclic ring with 3 carbon atoms, or R² is C₆₋₁₀-aryl optionallyindependently substituted by one or more groups selected fromC₁₋₆-alkyl, C₁₋₆-haloalkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, CN, halogen,OR^(2.8), COOR^(2.8), COR^(2.10), NHCOMe, CONR^(2.3)R^(2.4), a C₁₋₄alkylene group substituted by NR^(2.1)R^(2.2), or NR^(2.1)R^(2.2) or R²is C₆₋₁₀-aryl optionally independently substituted by one or more groupsselected from C₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene,C₃₋₇-cycloalkyl, a C₃₋₇-cycloalkyl-C₁₋₄-alkylene, C₆₋₁₀-aryl, and aheterocyclic C₃₋₁₀ ring, wherein these groups are each optionallysubstituted by one or more groups selected from C₁₋₆-alkyl,C₁₋₆-haloalkyl, COOR^(2.8), CN, halogen, OR^(2.8), NHCOR^(2.8), oxo, aC₃₋₁₀ heterocycle, a C₃₋₇-cycloalkyl-C₁₋₄ alkylene, a C₅₋₁₀ heterocycle-C₁₋₄-alkylene, and a NR^(2.1)R^(2.2)—C₁₋₄ alkylene, wherein: R^(2.8) isH, C₁₋₆-alkyl, C₆₋₁₀-aryl, or a NR^(2.1)R^(2.2)—C₁₋₄ alkylene group, andR^(2.10) is NHR^(2.10.1) or a heterocyclic C₃₋₁₀ ring optionallysubstituted by C₁₋₄-alkyl, wherein R^(2.10.1) is H, C₃₋₇-cycloalkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkyl, or C₁₋₆-alkyl-O—C₁₋₄-alkyl, orR² is C₆₋₁₀-aryl to which an aromatic or non-aromatic C₃₋₁₀ heterocycleis fused, or R² is an aromatic or non-aromatic heterocyclic C₃₋₁₀ ringoptionally substituted by one or more groups selected from halogen, OH,oxo, CN, C₁₋₆-alkyl, C₁₋₆-alkanol, C₆₋₁₀-aryl-C₁₋₆-alkylene,C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, COR^(2.11),C₃₋₇-cycloalkyl-C₁₋₄-alkylene, and C₃₋₁₀ heterocycle-C₁₋₄-alkylene,wherein R^(2.11) is a group selected from C₃₋₁₀heterocycle-C₁₋₄-alkylene, C₃₋₇-cycloalkyl, and a heterocyclic aromaticor non-aromatic C₃₋₁₀ ring, optionally substituted by C₁₋₆-alkyloptionally substituted by OH, CH₂OH, OMe, NH₂, a C₃₋₁₀ heterocycle, orNHCOO-^(t)Bu, or R² is C₂₋₆-alkenyl or a bicyclic ring, each optionallysubstituted by methyl, or NR¹R² is a heterocyclic ring optionallysubstituted by one or more groups selected from C₁₋₄-alkyl, OH, andC₁₋₄-alkanol; R³ is a group selected from a heterocyclic C₃₋₁₀ ring, aC₃₋₇-cycloalkyl, a bicyclic, fused aromatic or non-aromatic ring system,which optionally contains 1 to 4 heteroatoms selected from S, N, O, orit is C₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, andCH₂-benzo[1,3]dioxolyl, optionally substituted by one or more groupsselected from OH, halogen, C₁₋₆-alkyl, O—C₁₋₆-alkyl, C₁₋₆-haloalkyl, andCO—R^(3.1), or R³ is phenyl optionally substituted by one or more groupsselected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₄-haloalkyl,C₁₋₆-alkylene-NR^(3.1)R^(3.2), CN, COOR^(3.1), CONR^(3.1)R^(3.2),NR^(3.1)R^(3.2), NHCOR^(3.1), CF₃, OR^(3.1), halogen, NHCOR^(3.1), NO₂,SO₂NR^(3.1)R^(3.2), and C₁₋₆-alkylene-NHCOR^(3.1), wherein: R^(3.1) isH, C₁₋₆-alkyl; C₂₋₆-alkenyl, or C₂₋₆-alkynyl, optionally bridged, mono-or bicyclic C₃₋₁₀ heterocycle, or C₃₋₁₀ heterocycle-C₁₋₄-alkylene group,and R^(3.2) is H, C₁₋₆-alkyl, C₂₋₆-alkenyl, or C₂₋₆-alkynyl, or R³ is agroup of formula 1b

R^(3.3) is a heterocyclic C₃₋₁₀ ring optionally substituted by one ormore groups selected from C₁₋₆-alkyl, oxo, COR^(3.3.1), COR^(3.3.2),C₁₋₆-alkylene-R^(3.3.2), CH₂CO-pyrrolidine, and a heterocyclic C₃₋₁₀ring, wherein a sulfur atom optionally contained in the heterocyclicring is optionally in the form of the oxide or dioxide, wherein:R^(3.3.1) is C₁₋₆-alkyl, and R^(3.3.2) is NH₂, NH(C₁₋₆-alkyl), orN(C₁₋₆-alkyl)₂, or R^(3.3) is a bicyclic ring or heterocyclic spiroring, or R³ is a group of formula 1c

A is a bond or C₁₋₆-alkyl optionally substituted by oxo or NMe₂; R^(3.5)is H or C₁₋₆-alkyl; R^(3.5) is C₁₋₆-alkyl optionally substituted by oneor more groups selected from C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a C₃₋₁₀heterocycle, while this group is optionally substituted in each case bya group selected from OH, oxo, C₁₋₆-alkyl, O—C₁₋₆-alkyl, andC₁₋₆-haloalkyl, or a group selected from a heterocyclic C₃₋₁₀ ring and abicyclic ring, optionally substituted by one or more groups selectedindependently of one another from oxo, C₁₋₆-alkyl, OH, C₆₋₁₀-aryl, aheterocyclic C₃₋₁₀ ring, C₁₋₆-alkylene-R^(3.5.1),O—C₁₋₆-alkylene-R^(3.5.1), and NH—C₁₋₆-alkylene-R^(3.5.1), whereinR^(3.5.1) is a group selected from C₆₋₁₀-aryl and a heterocyclic C₃₋₁₀ring optionally substituted by C₁₋₆-alkyl; or R³ is a group of formula1d

D is C₂₋₄-alkynyl or an optionally bridged, bicyclic C₃₋₁₀-cycloalkylgroup, each optionally substituted by one or more groups selected fromC₁₋₆-alkyl, halogen, OH, C₁₋₆-haloalkyl, and O—C₁₋₆-alkyl, R^(3.6) ispyridinyl, or R³ is COR^(3.7), COCH₂R^(3.8), CONHR^(3.8), SO₂R^(3.8), ora heterocyclic group fused to a C₆₋₁₀-aryl group, each optionallysubstituted by methyl, or R³ is a group of formula 1e

R^(3.7) is H, C₁₋₆-alkyl, or C₆₋₁₀-aryl; R^(3.8) is a group selectedfrom C₁₋₆-alkyl, C₃₋₇-cycloalkyl, or a group selected from C₆₋₁₀-aryl, aheterocyclic C₃₋₁₀ ring, and a bicyclic ring, optionally substituted byone or more groups selected from C₁₋₆-alkyl, halogen,NR^(3.8.1)R^(3.8.2), C₆₋₁₀-aryl, and a heterocyclic C₃₋₁₀ ring, wherein:R^(3.8.1) is H or C₁₋₆-alkyl, and R^(3.8.2) is H or C₁₋₆-alkyl; R⁴ is H,C₁₋₄-alkyl, or oxo; R⁵ is H or C₁₋₄-alkyl; R⁶ is H or C₁₋₄-alkyl; R⁷ isH, C₁₋₄-alkyl, C₆₋₁₀-aryl, or OH; R⁸ is H, C₁₋₄-alkyl, C₆₋₁₀-aryl, orOH; or R⁷ and R⁸ together form oxo; or a pharmacologically acceptablesalt, enantiomer, hydrate, or solvate thereof.
 3. The compound offormula 1 according to claim 1, wherein: X is O, S, SO, or SO₂; R¹ is H,methyl, ethyl, or propyl; R² is H or C₁₋₆-alkyl optionally substitutedby one or more groups selected from CF₃, CN, OH, NMe₂, OMe, COOH, andCONMe₂, or R² is C₁₋₆-alkyl optionally substituted by one or more groupsselected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl,pyrrolidinyl, imidazolidinyl, pyrazolyl, imidazolyl, and pyridinyl, eachoptionally substituted by methyl or oxo; or R² is C₃₋₇-cycloalkyloptionally substituted by a group selected from methyl, OR^(2.3),CH₂OR^(2.3), COOH, CONR^(2.3)R^(2.4), CONH-^(t)Bu, O-benzyl,NR^(2.3)R^(2.4), and NHCOR^(2.5), wherein: R^(2.3) is H, methyl, or

R^(2.4) is H or methyl, and R^(2.5) is CH₂C(CH₃)₃, CH₂C(CH₃)₂(CH₂OH),cyclopentyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl, imidazolyl, orisoxazolyl; or R² is a group of formula 1a

Y is C₁₋₄-alkylene optionally substituted by one or two R^(2.7), andR^(2.7) are each independently C₁₋₄-alkyl, COOH, or CONH₂, or R^(2.7)together with one or two carbon atoms of Y forms a carbocyclic ring with3 carbon atoms; or R² is C₆₋₁₀-aryl optionally substituted by one ormore groups independently selected from methyl, tert-butyl, CN, F, Cl,Br, OH, OMe, OEt, O-phenyl, COOH, COOMe, COR^(2.10), NHCOMe, andmorpholine-substituted C₁₋₄-alkylene, wherein R^(2.10) is NH₂, NHMe,NH-^(i)Pr, NH-cyclopropyl, NHCH₂CH₂OMe, or a heterocyclic, non-aromaticC₃₋₁₀ ring containing one, two, or three heteroatoms selected fromoxygen and nitrogen; or R² is C₆₋₁₀-aryl optionally substituted byphenyl or a heterocyclic C₃₋₁₀ ring, each optionally substituted by oneor more groups selected from methyl, tert-butyl, COOH, COOMe, CN, F, Cl,Br, OH, OMe, OEt, and NHCOMe, and oxo; or R² is a heterocyclicnon-aromatic C₃₋₀ ring optionally substituted by benzyl or COR²⁻¹¹,wherein R^(2.11) is a group selected from cyclopentyl,tetrahydrofuranyl, furan, pyridyl, pyrrolyl, pyrazolyl, or imidazolyl,each optionally substituted by one or two methyl groups or by one ormore groups selected from CH₂C(CH₃)₃, C(CH₃)₂(CH₂OH), CH₂OMe,C(CH₃)₂NH₂, and C(CH₃)₂NHCOO-^(t)Bu; or R² is C₂₋₆-alkenyl, indanyl,1,2,3,4-tetrahydronaphthalyl, or 8-methyl-8-azabicyclo[3.2.1]octane; orNR¹R² is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, eachoptionally substituted by methyl; R³ is pyridinyl, pyrimidine, benzyl,or CH₂-benzo[1,3]dioxolyl; or R³ is phenyl optionally substituted byone, two, or three groups selected from methyl, CH₂NH₂, CN, COOH, CONH₂,CF₃, OH, F, Cl, Br, OMe, NHCOMe, NR^(3.1)COR^(3.2), CONR^(3.1)R^(3.2),NO₂, SONMe₂, and CH₂NHCOMe, wherein: R^(3.1) is H, C₁₋₆-alkyl, or anoptionally bridged, mono- or bicyclic C₃₋₁₀ heterocycle, and R^(3.2) isH or C₁₋₆-alkyl; or R³ is a group of formula 1b

R^(3.3) is piperidinyl, piperazinyl, or azepanyl, each optionallyindependently substituted by one or more groups selected from methyl,oxo, COCH₃, CONH₂, CH₂NEt₂, CH₂CH₂NMe₂, CH₂COpyrrolidine, pyridinyl,isothiazolidinyl-1,1-dioxide, and thiazolidinyl-1,1-dioxide, or R^(3.3)is a group of formula

R³ is a group of formula 1c

A is a bond or C₁₋₄-alkyl optionally substituted by oxo or NMe₂, R^(3.4)is H or methyl, and R^(3.5) is pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, cyclohexyl, imidazolyl, pyrazolyl, phenyl, pyridinyl,benzimidazolyl, imidazolidin-2-one, pyrrolidin-2-one, pyrrolidin-3-one,tetrahydrothiophene-1,1-dioxide, or 1-azabicyclo[2.2.2]octane, eachoptionally independently substituted by one or more groups selected frommethyl, ethyl, OH, phenyl, pyridinyl, pyrazolyl, pyrrolidinyl,(CH₂)_(o)—R^(3.5.1), O—(CH₂)_(o)—R^(3.5.1), and NH—(CH₂)_(o)—R^(3.5.1),wherein: o is 0, 1, or 2, and R^(3.5.1) is phenyl, pyrrolidinyl,piperidinyl, or imidazolidin-2-one, each optionally substituted bymethyl; or R³ is a group of formula 1d

D is C₂₋₄-alkynyl; R^(3.6) is pyridinyl; or R³ is COR^(3.7),COCH₂R^(3.8), CONHR^(3.8), SO₂R^(3.8), or a group of formula 1e

R^(3.7) is H, methyl, or phenyl, and R^(3.8) is isopropyl, cyclopropyl,cyclopentyl, cyclohexyl, pyrrolidinyl, pyrrolidin-2-one, furanyl,azabicyclo[2.2.2]octanyl, or a group selected from piperidinyl,pyrazolyl, imidazolyl, isoxazolyl, pyridinyl, phenyl, or benzyl, eachoptionally independently substituted by one or more groups selected frommethyl, chlorine, NH₂, NMe₂, phenyl, and morpholinyl; R⁴ is H, methyl,or oxo; R⁵ is H or methyl; R⁶ is H or methyl; R⁷ is H, methyl, or OH; R⁸is H, methyl, or OH; or R⁷ and R⁸ together form oxo; or apharmacologically acceptable salt, enantiomer, hydrate, or solvatethereof.
 4. The compound of formula 1 according to one of claims 1 to 3,wherein R¹ is H, or a pharmacologically acceptable salt, enantiomer,hydrate, or solvate thereof.
 5. The compound of formula 1 according toone of claims 1 to 3, wherein X is SO, or a pharmacologically acceptablesalt, enantiomer, hydrate, or solvate thereof.
 6. The compound offormula 1 according to one of claims 1 to 3, wherein R⁵, R⁶, R⁷, and R⁸are each H, or a pharmacologically acceptable salt, enantiomer, hydrate,or solvate thereof.
 7. The compound of formula 1 according to claim 1 to3, wherein R⁴ is H, or a pharmacologically acceptable salt, enantiomer,hydrate, or solvate thereof.
 8. The compound of formula 1 according toclaim 1, wherein: R² is C₆₋₁₀-aryl optionally independently substitutedby one or more groups selected from C₁₋₆-alkyl, C₁₋₄-haloalkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, CN, halogen, OR^(2.8), COOR^(2.8),COR^(2.10), NR^(2.8)R^(2.9), NHCOR^(2.8), SR^(2.8), SOR^(2.8),SO₂R^(2.8) and SO₂NR^(2.8)R^(2.9); or R² is C₆₋₁₀-aryl optionallyindependently substituted by one or more groups selected fromC₆₋₁₀-aryl-C₁₋₆-alkylene, C₅₋₁₀-heteroaryl-C₁₋₆-alkylene, C₆₋₁₀-aryl,and a heterocyclic C₃₋₁₀ ring, each optionally substituted by a groupselected from C₁₋₆-alkyl, C₁₋₆-haloalkyl, COOR^(2.8), CN, halogen,OR^(2.8), NHCOR^(2.8), oxo, a C₃₋₇-cycloalkyl-C₁₋₄ alkylene, aheterocycle-C₁₋₄ alkylene, and a NR^(2.1)R^(2.2)—C₁₋₄-alkylene, wherein:R^(2.8) is H, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, aNR^(2.1)R^(2.2)—C₁₋₄-alkylene, or C₆₋₁₀-aryl, R^(2.9) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, and R^(2.10) is NHR^(2.10.1),C₁₋₆-alkylene-O—C₁₋₄-alkyl, or a heterocyclic C₃₋₁₀ ring optionallysubstituted by C₁₋₄-alkyl, wherein R^(2.10.1) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, or C₃₋₇-cycloalkyl; or R² is C₆₋₁₀-aryl towhich an aromatic or non-aromatic C₃₋₁₀ heterocycle is fused; or R² isC₆₋₁₀-aryl optionally substituted by a group selected from C₆₋₁₀-aryland a heterocyclic C₃₋₁₀ ring, each optionally substituted by one ormore groups selected from C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₄-haloalkyl, CN, halogen, OR^(2.8), COOR^(2.8), COR^(2.10)NR^(2.8)R^(2.9), NHCOR^(2.8), SR^(2.8), SOR^(2.8), SO₂R^(2.8),SO₂NR^(2.8)R^(2.9), and oxo; or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 9. The compound of formula 1according to claim 1, wherein: R² is C₆₋₁₀-aryl optionally substitutedby one or more groups selected from C₁₋₄-alkyl, CN, halogen, OR^(2.8),COOR^(2.8), COR^(2.10), and NHCOMe, wherein: R^(2.8) is C₁₋₄-alkyl orC₆₋₁₀-aryl; R^(2.10) is NHR^(2.10.1) morpholinyl, or methylpiperazinyl;and R^(2.10.1) is H, cyclopropyl, or C₁₋₄-alkyl optionally substitutedby one or more groups selected from O—C₁₋₄-alkyl, OH, or C_(6.10)-aryl;or R² is C₆₋₁₀-aryl optionally substituted by a group selected fromphenyl and a heterocyclic C₃₋₁₀ ring, each optionally substituted byC₁₋₄-alkyl, COOR^(2.8), CN, halogen, OR^(2.8), NHCOMe, or oxo; or apharmacologically acceptable salt, enantiomer, hydrate, or solvatethereof.
 10. The compound of formula 1 according to claim 1, wherein: R²is C₁₋₆-alkyl, C₂₋₆-alkenyl, or C₂₋₆-alkynyl, each optionallysubstituted by C₁₋₆-haloalkyl, CN, OR^(2.1), NR^(2.1)R^(2.2),NHCOR^(2.1), SR^(2.1), SOR^(2.1), SO₂R^(2.1), SO₂NR^(2.1)R^(2.2),COOR^(2.1), or CONR^(2.1)R^(2.2), each optionally substituted byC₃₋₇-cycloalkyl, C₆₋₁₀-aryl, or a heterocyclic C₃₋₁₀ ring, eachoptionally substituted by one or more groups selected from C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, and oxo, wherein: R^(2.1) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, and R^(2.2) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 11. The compound of formula 1according to claim 1, wherein: R² is C₁₋₆-alkyl optionally substitutedby C₁₋₄-haloalkyl, CN, OR^(2.1), NR^(2.1)R^(2.2), COOR^(2.1), orCONR^(2.1)R^(2.2), or optionally substituted by C₃₋₇-cycloalkyl,C₆₋₁₀-aryl, or a heterocyclic, aromatic C₃₋₁₀ ring, each optionallysubstituted by methyl or oxo, wherein: R^(2.1) is H or C₁₋₄-alkyl; andR^(2.2) is H or C₁₋₄-alkyl, or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 12. The compound of formula 1according to claim 1, wherein: R² is C₆₋₁₀-aryl optionally independentlysubstituted in the meta position by one or more groups selected fromC₁₋₄-alkyl, CN, halogen, OR^(2.8), COOR^(2.8), COR^(2.10), and NHCOMe,wherein: R^(2.8) is C₁₋₄-alkyl or C₆₋₁₀-aryl, R^(2.10) is NHR^(2.10),morpholinyl, or methylpiperazinyl, and R^(2.10.1) is H, cyclopropyl, orC₁₋₄-alkyl, wherein the C₁₋₄-alkyl is optionally independentlysubstituted by one or more groups selected from O—C₁₋₄-alkyl, OH, andC₆₋₁₀-aryl; or R² is NH(R^(2.10.1)) or cyclohexyl; or NR¹R² ispyrrolidine and piperazine, each optionally substituted by one or moregroups selected from C₁₋₄-alkyl, OH, and C₁₋₄-alkanol or apharmacologically acceptable salt, enantiomer, hydrate, or solvatethereof.
 13. The compound of formula 1 according to claim 1, wherein: R³is phenyl optionally substituted by one or more groups selected fromC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₄-haloalkyl,C₁₋₆-alkylene-N^(3.1)R^(3.2), CN, halogen, OR^(3.1), COOR^(3.1),CONR^(3.1)R^(3.2), NR^(3.1)R^(3.2), NHCOR^(3.1), NO₂, SR^(3.1),SOR^(3.1)l, SO₂R^(3.1), SO₂NR^(3.1)R^(3.2), andC₁₋₆-alkylene-NHCOR^(3.1), wherein: R^(3.1) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, and R^(3.2) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl; or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 14. The compound of formula 1according to claim 1, wherein: R³ is phenyl optionally substituted inthe para position by C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₁₋₄-haloalkyl, C₁₋₆-alkylene-NR^(3.1)R^(3.2), CN, halogen, OR^(3.1),COOR^(3.1), CONR^(3.1)R^(3.2), NR^(3.1)R^(3.2), NHCOR^(3.1), NO₂,SR^(3.1), SOR^(3.1), SO₂R^(3.1), SO₂NR^(3.1)R^(3.2), orC₁₋₆-alkylene-NHCOR^(3.1), wherein: R^(3.1) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl, and R^(3.2) is H, C₁₋₆-alkyl,C₂₋₆-alkenyl, or C₂₋₆-alkynyl; or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 15. The compound of formula 1according to claim 1, wherein: R³ is a group of formula 1b

R^(3.3) is a heterocyclic C₃₋₁₀ ring optionally independentlysubstituted by one or more groups selected from C₁₋₆-alkyl, oxo,COR^(3.3.1), COR^(3.3.2), C₁₋₆-alkylene-R^(3.3.2) CH₂COpyrrolidine, anda heterocyclic C₃₋₁₀ ring, wherein a sulfur atom optionally contained inthe heterocyclic C₃₋₁₀ ring is optionally present as the oxide ordioxide, wherein: R^(3.3.1) is C₁₋₆-alkyl, and R^(3.3.2) is NH₂,NH(C₁₋₆-alkyl), or N(C₁₋₆-alkyl)₂; or R^(3.3) is a bicyclic ring or aheterocyclic spiro ring; or a pharmacologically acceptable salt,enantiomer, hydrate, or solvate thereof.
 16. The compound of formula 1according to claim 1, wherein: R³ is a group of formula 1c

A is a bond or C₁₋₆-alkyl optionally substituted by oxo or NMe₂; R^(3.4)is H or C₁₋₆-alkyl; R^(3.5) is C₁₋₆-alkyl optionally substituted by agroup selected from C₃₋₇-cycloalkyl, C₆₋₁₀-aryl, and a C₅₋₁₀heterocycle, each optionally substituted by one or more groups selectedfrom halogen, OH, oxo, C₁₋₆-alkyl, O—C₁₋₆-alkyl, C₁₋₆-haloalkyl, aheterocyclic C₃₋₁₀ ring, and a bicyclic ring, wherein each of thesegroups is optionally independently substituted by one or more groupsselected from oxo, C₁₋₆-alkyl, OH, C₆₋₁₀-aryl, a heterocyclic ring,C₁₋₆-alkylene-R^(3.5.1), O—C₁₋₆-alkylene-R^(3.5.1), andNH—C₁₋₆-alkylene-R^(3.5.1), wherein R^(3.5.1) is C₆₋₁₀-aryl or aheterocyclic C₃₋₁₀ ring, each optionally substituted by C₁₋₆-alkyl, or apharmacologically acceptable salt, enantiomer, hydrate, or solvatethereof.
 17. The compound of formula 1 according to claim 1, wherein: R³is a group of formula 1d

D is C₂₋₄-alkynyl; and R^(3.6) is pyridinyl, or a pharmacologicallyacceptable salt, enantiomer, hydrate, or solvate thereof.
 18. Thecompound of formula 1 according to claim 1, wherein: R³ is a group offormula 1e

R^(3.7) is H, halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, orC₁₋₆-haloalkyl; R^(3.8) is H, OH, halogen or a group selected fromC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-haloalkyl, O—C₁₋₆-alkyl,C₆₋₁₀-aryl, a heterocyclic C₃₋₁₀ ring, and a bicyclic ring, eachoptionally independently substituted by one or more groups selected fromhalogen, C₁₋₆-alkyl, OH, C₁₋₆-haloalkyl, and O—C₁₋₆-alkyl, or apharmacologically acceptable salt, enantiomer, hydrate, or solvatethereof.
 19. A pharmaceutical formulation comprising a compound offormula 1 according to one of claims 1 to 18 and a pharmaceuticallyacceptable excipient.